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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgmant
  8. DISCLOSURE
  9. REFERENCES

Three double-blind, placebo-controlled, three-parallel-group, multicenter phase 3 trials were conducted to assess the efficacy and safety of CP-945,598 for weight loss and weight-loss maintenance. Two trials were designed to be 2 years in duration (in obese and overweight patients) and one as a 1-year study (in obese and overweight patients with type 2 diabetes). However, the 2-year trials and the CP-945,598 development program were terminated before completion due to changing regulatory perspectives of CB1 receptor-related drugs. In total, 1,253 and 2,536 participants in the two 2-year multinational and North American studies were randomized to 10-mg CP-945,598 (n = 360; 718); 20-mg CP-945,598 (n = 534, 1,084) and placebo (n = 359, 734), respectively; and 975 participants were randomized to 10-mg CP-945,598 (n = 318); 20-mg CP-945,598 (n = 320); and placebo (n = 337) in the 1-year multinational diabetes trial. Baseline demographics were similar between treatment groups within each trial. One year of treatment with CP-945,598 resulted in a dose-related mean percentage reduction from baseline body-weight in all trials. A significant proportion of all participants also achieved 5% and 10% weight loss after 1 year. In participants with mainly well-controlled type 2 diabetes, the combination of lifestyle and CP-945,598 induced substantial improvements in glycemic control. The most frequent adverse events (AEs) for CP-945,598 were: diarrhea, nausea, nasopharyngitis, and headache. Self-reported experiences of anxiety and suicidal thoughts were higher with CP-945,598 than placebo, as were the incidence of depression and depressed mood. However, the reported increases in psychiatric symptoms were not consistently dose dependent.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgmant
  8. DISCLOSURE
  9. REFERENCES

The limited success of lifestyle modification interventions for long-term weight-loss maintenance in obesity and its associated comorbidities has driven the search for effective and safe pharmacotherapy. The endocannabinoid system is a neuromodulatory system that has been identified as a target for pharmacologic treatment in the management of obesity (1); it is comprised of CB1 and CB2 cannabinoid receptors, endogenous ligands, and enzymes for ligand biosynthesis and inactivation (2,3). CB1 receptors are located in the central nervous system and peripheral tissues (2,4,5), and CB2 receptors are mainly located in certain peripheral immune tissues and cells (2,6). The endocannabinoid system has been shown to have a role in the regulation of energy balance and food intake (7,8), mostly through the function of CB1 receptors. There are several examples of genetic syndromes of obesity in animals in which the endocannabinoid system is dysregulated (9).

The CB1 cannabinoid receptor antagonist rimonabant was developed for the management of obesity and related risk factors associated with obesity in humans (10). Addition of rimonabant to a weight-loss program increased weight loss and weight-loss maintenance by 1.8 kg at 5-mg dose and 6.6 kg at 20-mg dose in nondiabetic individuals (11); in those with type 2 diabetes, weight loss at 1 year was 2.3 kg compared with 1.4 kg with placebo (12).

Rimonabant was granted marketing authorization in Europe as an adjunct to diet and exercise for the treatment of obese patients by the European Commission on 19 June 2006 (13). However, due to reports of adverse events (AEs) including psychiatric symptoms, along with postmarketing evidence that the effectiveness of rimonabant from real-world experience was typically lower than that in clinical trials, the European Medicines Agency recommended the suspension of the marketing of rimonabant (14). Marketing was suspended in November 2008, and the marketing authorization was withdrawn on 16 January 2009 (13).

Design strategies to find conformationally restricted analogs of the diarylpyrazole rimonabant, with a view to adopt its bioactive conformation, with improved potency, low metabolic clearance with good solubility, and good central nervous system penetration without the potential to generate reactive metabolites resulted in the discovery of CP-945,598. This molecule is a purine derivative CB1 receptor antagonist that demonstrates subnanomolar potency at human CB1 receptors in binding and functional assays and reduces food intake and energy expenditure in rats (15).

Three phase 3 trials were conducted to evaluate the long-term efficacy and safety of CP-945,598 in the treatment of overweight or obese patients with or without type 2 diabetes. In compliance with the U.S. Food and Drug Administration and Good Clinical Practice guidelines (16) and to maximize participant motivation and retention, all three trials included a comprehensive diet and exercise program involving both behavioral modification and the support of a dietitian.

Doses of 10- and 20-mg once daily (q.d.) orally (p.o.) were selected for evaluation based on the results of pharmacokinetic/pharmacodynamic analyses of weight loss in a 6-month study of CP-945,598 (17). Weight-loss efficacy of at least 3% placebo-adjusted weight loss at 1 year was expected with the 10-mg dose and ≥5% placebo-adjusted percent weight loss at 1 year with the 20-mg dose.

Of the three trials, two were designed to be 2 years in duration and one as a 1-year study. All three trials included obese and overweight patients, and the patients in the 1-year trial also had a diagnosis of type 2 diabetes. On 3 November 2008, before completion of the 2-year phase 3 studies, Pfizer, as sponsor, elected to discontinue the three trials and the CP-945,598 development program. The decision was based on changing regulatory perspectives with regard to the risk/benefit profile of CB1 receptor-related drugs and the likely difficulties of obtaining regulatory approval for them. The majority of patients in the three trials had completed 1 year of dosing with CP-945,598. The results of the completed components of these three trials are presented here for full disclosure and to contribute to the scientific understanding of the role of CB1 receptors in weight management.

Traditionally, weight-loss studies have used a placebo run-in phase to acclimate patients to the nonpharmacologic weight-loss program, and exclude patients who would not readily commit to the study. A placebo run-in period was not included in these studies because: (i) simultaneous initiation of the nonpharmacologic weight-loss program and drug treatment more closely mimics current clinical practice for obesity and provides a more accurate baseline for the clinical trial; (ii) maximizing the potential for weight loss across all groups during the treatment phase of the trials should also translate into better patient retention; (iii) elimination of patients during a placebo weight loss run-in introduces bias (by eliminating some participants) and reduces generalizability of the study results; (iv) a similar approach has been recently used in several large weight-loss trials designed by leading experts and sponsored by governmental agencies (18,19).

Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgmant
  8. DISCLOSURE
  9. REFERENCES

Study design

All three trials were double-blind, placebo-controlled, three-parallel-group, multicenter studies of CP-945,598 for the assessment of weight loss and weight-loss maintenance. Two trials were designed to be 2 years in duration (i.e., MN-1019 and NA-1025 in obese and overweight patients), and one trial was designed as a 1-year study in obese and overweight patients with type 2 diabetes (DM-1022). Studies MN-1019 and DM-1022 were multinational global studies. Study NA-1025 was conducted in the United States and Canada.

Participants

Men and women, aged 18–70 years, with a BMI of ≥30 kg/m2 for participants without comorbidities and ≥27 kg/m2 for those with comorbidities such as hypertension or dyslipidemia, were recruited from clinics or by advertisement.

In DM-1022, participants all had a diagnosis of type 2 diabetes mellitus (as defined by the American Diabetes Association) for at least 4 months with stable oral antidiabetes regimens (either single or combined) from the following list: sulfonylurea, metformin, thiazolidinedione, sitagliptin, meglitinides, or α-glucosidase inhibitors. Patients on insulin or incretins and those with screening glycosylated hemoglobin (HbA1c) <6.5% and >10%, or fasting plasma glucose levels >270 mg/dl (15 mmol/l) were excluded.

Participants with an unstable medical condition, such as significant cardiovascular disease, dyslipidemia, renal disease, or with a cardiovascular event or intervention during the past 6 months were excluded. Those with a prior history of malignancy during the last 5 years were excluded, as were women who were pregnant or lactating.

Other exclusion criteria included: seizure disorders not controlled by current antiepileptic medication or use of an antiepileptic medication known to affect weight (unless the dose and the patient's weight had been stable for at least 6 months). Also excluded were participants with: any neurologic disorder which was acute, chronic relapsing, progressive, or had an unpredictable course; unstable smoking habits including those who stopped smoking within the last 6 months; any history of drug use or alcoholism or fluctuation in weight >5%, participation in a formal weight-loss program, or use of prescription drugs for weight loss within 3 months prior to screening. Use of marijuana or its derivatives were also excluded.

Patients with a history or current diagnosis of psychiatric conditions, including depression, eating disorders, psychoses, or suicide attempt were also excluded.

In addition, in MN-1019 and NA-1025, patients with diabetes or fasting plasma glucose levels ≥126 mg/dl were excluded.

Interventions

All trial participants were provided with a 7-day food and physical activity log after the first screening visit, and received their first dose of study drug after the second screening visit 7 days later, when they were advised on a nonpharmacologic weight-loss program during the first 6–9 months of the trial, including strategies likely to reduce weight regain after the initial weight loss. It comprised a 500–750 kcal/day deficit, a physical activity (goal of walking for 60–90 min/day), and simple cognitive-behavioral lifestyle modification advice. For DM-1022, the program was delivered and reinforced through face-to-face contact with a dietitian at baseline/randomization (day 1) and then at week 2, and months 1, 3, 4, 5, 6, 9, and 11, and telephone contact was interspersed between these visits during week 2, and months 1.5, 3.5, 4.5, 5.5, 7, 8, and 10. Face-to-face contact with the dietitian in MN-1019 occurred at baseline/randomization (day 1), then biweekly during the first 6 months and monthly thereafter. In NA-1025, face-to-face contact with the dietitian was scheduled to occur on day 1, week 2, and months 1, 2, 3, 4, 5, 6, 8, 10, 12, 13, 15, 17, 18, 20, 22, and 24. Telephone contact with the dietitian for both the MN-1019 and NA-1025 studies was scheduled to occur at months 1.5, 2.5, 3.5, 4.5, 5.5, 7, 9, 11, 14, 16, 19, 21, and 23. However, due to early termination of the CP-945,598 development program, few participants attended the last few scheduled clinic visits during the second year; for this reason, data are not reported beyond month 18 for MN-1019 and month 20 for NA-1025.

Participants were randomly assigned to one of the treatment groups to receive one of the following regimens: CP-945,598 10-mg p.o. q.d., CP-945,598 20-mg p.o. q.d., or placebo. In DM-1022, the allocation ratio was 1:1:1, and in MN-1019 and NA-1025 the allocation ratio was 1:1.5:1 (10 mg, 20 mg, placebo respectively). The increased ratio of participants receiving CP-945,598 20-mg in the nondiabetes studies was prespecified to maximize the number of patients receiving the dose, thought most likely to form the basis of approval globally.

Body weight was recorded using calibrated scales, with participants wearing light clothing and no shoes, at approximately the same time of day and under standardized conditions at every clinic visit. Clinic visits were scheduled to occur at screening, and then at day 1, week 2, and months 1, 2, 3, 4, 5, 6, 9, 11, 12, and 13 in DM-1022, and at day 1, week 2, and months 1, 2, 3, 4, 5, 6, 8, 10, 12, 13, 15, 17, 18, 20, 22, and 24 in MN-1019 and NA-1022.

Efficacy outcome measures

The primary efficacy end point in all trials was change in body weight from baseline to week 52. Secondary end points included the percentage of patients with ≥5% weight loss and ≥10% weight loss at 1 year and changes in HbA1c from baseline in DM-1022.

Safety evaluations

Safety and tolerability were assessed using monitoring of AEs, vital sign measurements (blood pressure and pulse rates), clinical laboratory measurements, and 12-lead electrocardiograms. The Generalized Anxiety Disorder Questionnaire (GAD-7) was used to evaluate anxiety and the Patient Health Questionnaire (PHQ-9) was used to evaluate depression at various time points throughout the three studies.

Statistical analysis

The sample size in each trial was calculated to achieve at least 90% power to reject the null hypothesis of zero treatment effect based on a dropout rate of 25% in the first year and 15% in the second year.

The primary efficacy end point of change from baseline (as a percentage of baseline measurements) in body weight measured after 1 year of treatment was established by means of tests of the null hypothesis of no treatment effect, carried out at the 0.05 (two-sided) level of significance, comparing the 10-mg and the 20-mg CP-945,598 treatment groups with the placebo group.

The predefined populations were as follows: (i) full analysis set (FAS): participants who took at least one dose of assigned study medication, had a valid baseline measurement, and at least one valid post-treatment weight measurement (this FAS analysis differs from a traditional intent-to-treat analysis in that participants who were off-drug, in-study (ODIS), at the time of the observation were excluded); (ii) per protocol completers (PPC): protocol adherent participants who completed 12 months of treatment for the 1-year analyses; and (iii) FAS with ODIS subset: observations made on participants who, either for reasons of personal choice or medical necessity, discontinued the study medication but agreed to continue participating in the study by undergoing study tests and measurements are called ODIS observations. These observations were excluded from the primary FAS data set. When they are included, the data set is identified as FAS plus ODIS.

Percentage change from baseline body weight was analyzed by linear models fit by ordinary least squares to the FAS subset using last observation carried forward (LOCF) to the 1-year time point, and to the 1-year PPC subset, and by mixed-model repeated measures fit to the FAS data over the course of the first year. The frequency of 5% and 10% responses at the 1-year time point in the 10-mg and 20-mg PPC groups were analyzed by means of the Cochran–Mantel–Haenszel method.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgmant
  8. DISCLOSURE
  9. REFERENCES

Participants

In total, 1,919 patients were screened for DM-1022 and 975 were randomized to treatment, 1,663 overweight or obese patients were screened for MN-1019 and 1,253 were randomized, and 3,931 obese or overweight patients were screened for NA-1025 and 2,536 were randomized to treatment. The randomization and progress of the participants through all the trials are shown as a modified CONSORT diagram (Figure 1).

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Figure 1. Participant disposition. AE, adverse event; FAS, full analysis set; PPC, per protocol completers.

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Baseline demographics were similar between treatment groups within each trial (Table 1). In DM-1022, the mean ages for each treatment group were slightly higher, and there were a greater proportion of male participants in comparison with the treatment groups for patients without diabetes (MN-1019 and NA-1025). The ratio of participants in terms of race also differed slightly between trials, but was comparable for treatment groups within trials. Mean weight and BMI at baseline were similar between treatment groups and across all three studies. Median glucose levels, mean duration of diabetes, and mean HbA1c measurements at baseline were also similar between treatment groups in DM-1022.

Table 1.  Baseline characteristics
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Weight loss

CP-945,598 resulted in greater mean and dose-related weight loss from baseline/randomization over the first 12 months of treatment in comparison with placebo in each of the FAS populations of the three trials (Figure 2). The mean percentage changes from baseline at 12 months were −2.80, −5.62, and −5.33 for placebo, −4.76, −7.30, and −6.98 for 10-mg CP-945,598, and −6.21, −8.05, and −8.04 for 20-mg CP-945,598, respectively, for DM-1022, MN-1019, and NA-1025 (Figure 2). Due to early study termination of the two 2-year trials, the interpretation of the data beyond the first 12 months of treatment is extremely limited. The mean change from baseline at 12 months for the LOCF population is also shown in Figure 2.

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Figure 2. Percent change in body weight over time (full analysis set). For MN-1019 and NA-1025, the number of participants was small at the end of the second year due to program termination; therefore, data values are not shown beyond month 18 for MN-1019 and month 20 for NA-1025. The dotted lines represent data collected after the first 12 months of treatment. The interpretation of these data is limited due to early study termination. LOCF, last observation carried forward.

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The ordinary least squares and repeated measures treatment comparisons of percentage change in body weight at 12 months for the FAS (LOCF) population and the ordinary least squares analysis of the PPC population at 1 year are shown in Table 2. These treatment effects are robust; ordinary least squares analysis of treatment comparisons for the FAS with ODIS population (data not shown) was very similar to the FAS (LOCF) data with P values for treatment (both 10-mg and 20-mg CP-945,598) difference from placebo in the FAS with ODIS participants P < 0.0001, except for NM-1019, in which 10-mg CP-945,598 group vs. placebo was P = 0.0029.

Table 2.  Analysis of percent change in body weight (%) at 1 year
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Based on the FAS (LOCF) data, ∼40% of the participants in the 10-mg CP-945,598 group in the two nondiabetes studies (i.e., MN-1019 and NA-1025) and 34% of the patients with diabetes (i.e., DM-1022) achieved at least 5% weight loss (Figure 3). There was an even greater number of FAS (LOCF) participants achieving 5% weight loss at 1 year with 20-mg CP-945,598 (MN-1019, 51.6%; NA-1025, 48.3%; and DM-1022, 44.6%; Figure 3). In all three trials, the proportion of these participants who achieved at least 5% weight loss and at least 10% weight loss at 1 year was significantly greater in the active treatment groups than in the placebo groups. As with mean weight change over the first 12 months, these results also demonstrate a dose-dependent weight loss (Figure 3). The proportion of participants who achieved at least 5% and 10% weight loss at 12 months within studies MN-1019 and NA-1025 were very similar.

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Figure 3. Proportion of participants with at least 5% and 10% weight loss at 1 year (full analysis set (LOCF)). CI, confidence interval; LOCF, last observation carried forward; OR, odds ratio.

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For participants who remained compliant (PPC population), over half the participants without diabetes achieved at least 5% weight loss at 1 year in the 10-mg CP-945,598 group and was as high as 60% across all three trials with 20-mg CP-945,598 (Table 3). Dose-dependent trends were evident across the three trials for the PPC population at 1 year for participants achieving at least 10% weight loss at 1 year (Table 3).

Table 3.  Per protocol completer (PPC) participants achieving at least 5% and 10% weight loss at 1 year
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Waist circumference data were consistent with weight loss in each of the three trials. A kilogram of weight loss corresponded to ∼1 cm of reduced waist circumference at 12 months. Mean changes from baseline waist (cm) at 12 months were −4.2, −6.1, −5.2 for placebo; −6.7, −6.9, and −6.4 for 10-mg CP-945,598; and −5.7, −7.7, and −7.1 for 20-mg CP-945,598, respectively, for DM-1022, MN-1019, and NA-1025.

At the end of study, the mean ± s.d. change in HbA1c in DM-1022 was −0.39 ± 0.95 for placebo, −0.62 ± 1.07 for 10-mg CP-945,598, and −0.71 ± 0.94 for 20-mg CP-945,598 (Figure 4). HbA1c was not measured for obese participants without diabetes (MN-1019 and NA-1025) but median changes in glucose from baseline to last observation for active treatment groups were in the range of 0 to −4 mg/dl in both MN-1019 and NA-1025. Other median changes from baseline to last observed biochemical data for all three studies across active treatment groups were: high-density lipoprotein cholesterol (median change ranged from an increase of 1 to 3 mg/dl); low-density lipoprotein cholesterol (median change ranged from −6 to 3 mg/dl); and triglycerides (median change ranged from −14 to −6 mg/dl).

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Figure 4. Mean percentage change in glycosylated hemoglobin (HbA1c) from baseline (DM-1022 study). LOCF, last observation carried forward.

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Outcomes of GAD-7 and PHQ-9 questionnaires

GAD-7 outcomes. Mean baseline total scores for the GAD-7 questionnaire were 2.7 ± 3.3 (n = 311) for 10-mg CP-945,598 and 2.7 ± 3.2 (n = 305) for 20-mg CP-945,598 vs. 2.7 ± 2.9 (n = 325) for placebo in DM-1022. In MN-1019, mean baseline total scores were 2.7 ± 2.8 (n = 349) for 10-mg CP-945,598 and 2.9 ± 3.0 (n = 522) for 20-mg CP-945,598 vs. 2.6 ± 2.9 (n = 353) for placebo, respectively. In NM-1025, mean baseline scores were 1.4 ± 2.0 (n = 682) for 10-mg CP-945,598 and 1.4 ± 2.2 (n = 1,044) for 20-mg CP-945,598 vs. 1.4 ± 2.1 (n = 699) for placebo.

The proportion of participants who had a total score ≥10 (indicating significant anxiety) at any time was 18% in the 10-mg CP-945,598 group and 14.4% in the 20-mg CP-945,598 group vs. 8.9% in the placebo group in DM-1022. In MN-1019, 12% of participants in the 10-mg CP-945,598 group, 14.8% in the 20-mg CP-945,598 group had a total score ≥10 at any time vs. 10.8% in the placebo group. In NM-1025 the proportion of participants who had a total score of ≥10 on the GAD-7 at any time were 6.7% in the 10-mg CP-945,598 group, 7.1% in the 20-mg CP-945,598 group, and 8.4% in the placebo group.

PHQ-9 outcomes. The proportion of participants who, on at least one occasion, admitted to suicidal thoughts (item 9 on the PHQ-9 questionnaire) was slightly higher in the CP-945,598 treatment groups compared with the respective placebo groups with a dose-dependent increase in DM-1022 (3.7%, 3.9%, and 4.9%, respectively, for placebo, 10-mg CP-945,598, and 20-mg CP-945,598). The odds ratios for active treatment compared with placebo in DM-1022 were 1.05 (confidence interval (CI): 0.46, 2.37) and 1.35 (CI: 0.62, 2.94) for the 10-mg and 20-mg CP-945,598 groups, respectively. In MN-1019, the proportion of participants who endorsed item 9 was 3.2% in the 10-mg CP-945,598 group compared with 4.0% in the 20-mg CP-945,598 group and 0.8% in the placebo group. The odds ratio for MN-1019 = 3.8 (95% CI: 1.05, 13.73) for 10-mg CP-945,598 vs. placebo, and odds ratio = 4.9 (CI: 1.45, 16.55) for 20-mg CP-945,598 vs. placebo. In NA-1025, the proportion of participants who endorsed item 9 was higher in the 10-mg CP-945,598 group (3.8%) than in the 20-mg CP-945,598 group (1.5%) compared with 1.3% in the placebo group. The odds ratios for active treatment compared with placebo in NA-1025 were 3.04 (CI: 1.41, 6.53) and 1.19 (CI: 0.52, 2.71) for the 10-mg and 20-mg CP-945,598 groups, respectively.

Safety

The number of treatment discontinuations and dose reductions or temporary withdrawals from study medication was higher in the active treatment groups compared with the placebo groups in all three trials; most notably at 20-mg CP-945,598 (Table 4). Serious AEs were comparable between the 10-mg CP-945,598 groups and placebo within each study, but were slightly more frequent with 20-mg CP-945,598 in the nondiabetes studies (MN-1019 and NA-1025). There were three deaths across the three trials; one in the placebo group in the DM-1022 study on day 40 due to natural causes (probably due to arteriosclerotic disease identified at autopsy), one in the placebo group in the NA-1025 study on day 482 due to morbid obesity and obstructive sleep apnea, and one in the 10-mg CP-945,598 group in the MN-1019 study on day 385 due to myocardial infarction in a patient with ovarian cancer.

Table 4.  Adverse events (AEs) and most common AEs ≥5% in any treatment group in any trial
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The most commonly reported AEs for the active treatment were: diarrhea, nausea, nasopharyngitis, upper respiratory tract infection, and headache (Table 4). In most cases, these AEs occurred more frequently in patients treated with active drug than in those treated with placebo. The incidence of depression and depressed mood was more commonly reported in participants on active drug than on placebo in all three trials, but was similar between the 10-mg and 20-mg CP-945,598 treatment groups within each trial (Table 4).

The numbers of participants who discontinued from the study due to AEs (whether related or unrelated to the study) are shown in Figure 1. The study discontinuations were due to a variety of AEs for each of the treatment groups across all three trials, and the vast majority of AE types were cited only once as the cause for discontinuation. There were more study discontinuations due to psychiatric disorders (e.g., agitation; depression; suicidal ideation; panic attack) for participants on study drug than placebo in the NA-1025 and MN-1019 trials, but similar numbers across the three treatment groups in the DM-1022 trial. Of the psychiatric disorders, depression was the most common cause of study discontinuation. Study discontinuation due to gastrointestinal disorders was also slightly more common for the two active treatment groups than placebo across all three trials. Of gastrointestinal disorders, nausea was the most common cause of study discontinuation. Other types of AEs that were identified more than once in any treatment group as the reason for discontinuation were irritability and breast cancer.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgmant
  8. DISCLOSURE
  9. REFERENCES

These phase 3 trials show that CP-945,598 treatment increased weight loss in a dose-related manner and supported weight-loss maintenance in both diabetic and nondiabetic participants. Furthermore, a more intensive and effective lifestyle intervention program was employed compared to many other antiobesity pharmacotherapy trials (20). This, as well as the absence of any “dilution” from a run-in period before randomization, produced nearly twice the weight loss with placebo than that seen in other antiobesity clinical trials. Nevertheless, an additional weight loss effect of CP-945,598 was observed.

There was a remarkable consistency in outcomes across the three trials; mean weight-loss was greater after 1 year of treatment for both doses of CP-945,598 compared with placebo. Weight appeared to stabilize following 6–8 months of treatment in all three trials. There was also greater mean weight loss with 20-mg CP-945,598 than with 10-mg CP-945,598 in each of the trials and each analysis/subpopulation combination.

The proportion of FAS (LOCF) participants achieving at least 5% and at least 10% weight loss at 1 year was also greater for the active treatment groups in comparison with placebo, and a dose-dependent effect was evident across all three trials. There was also a statistically significant difference between the proportion of placebo participants achieving both 5% and 10% weight loss in the PPC population in the nondiabetic populations (MN-1109 and NA-1025), but the difference was only statistically significant at the higher dose (20-mg CP-945,598 vs. placebo) in the diabetes trial (DM-1022) for 5% and 10% weight loss.

Although the predefined analyses populations in these trials differed slightly from the intent-to-treat population that was used for the analyses of the rimonabant trials, the active treatments in the trials reported here and the rimonabant trials resulted in similar weight loss at 1 year, at least when considering the FAS (LOCF) data (which is most similar to the intent-to-treat population). The proportion of participants achieving 5% weight loss at 1 year in the FAS (LOCF) population of the MN-1019 trial (44.4% for 10-mg and 51.6% for 20-mg CP-945,598; Figure 3) was comparable to that reported in the Rimonabant in Obesity–Europe study intent-to-treat population (33.2% for 5-mg and 50.9% for 20-mg rimonabant) (11). Similar results were shown for the NA-1025 study (40.4% for 10-mg and 48.3% for 20-mg CP-945,598; Figure 3). The proportion of FAS (LOCF) participants with at least 5% weight loss at 1 year in the DM-1022 trial was also comparable for active treatment (33.7% for 10-mg and 44.6% for 20-mg CP-945,598; Figure 3) to that reported in the Rimonabant in Obesity–diabetes study (21.7% for 5-mg and 49.4% for 20-mg rimonabant) (12).

The CP-945,598 trials importantly showed that a greater proportion of FAS (LOCF) participants achieved ≥5% weight loss in the placebo groups than in the rimonabant trials: 22.2% in DM-1022 vs. 14.5% in the rimonabant diabetes trial (12); and 33.4% in MN-1019 and 31.4% in NA-1025 vs. 19.2% in the rimonabant in Obesity trial (11). The most likely explanation for this is the comprehensive dietary and lifestyle advice (specifically, the high degree of interaction with a dietitian) delivered to participants in the trials presented here. This more intense lifestyle modification program may have reduced the placebo-subtracted difference in weight between the active treatment groups and the placebo group.

The participants who remained compliant during the trials reported here (PPC participants at 1 year) achieved greater weight loss. More than half of the nondiabetic participants (in MN-1019 and NA-1025 studies) achieved 5% weight loss at 1 year on active treatment and one-third of the diabetic participants (in DM-1022) achieved this goal (Table 3). The proportion of PPC participants achieving 5% weight loss at 1 year was 60% across all three trials with 20-mg CP-945,598 (Table 3).

Several studies have shown that people with diabetes lose less weight than those without diabetes (21,22). With CP-945,598, participants with diabetes on placebo in the DM-1022 study, lost less weight compared with the trials in nondiabetics (mean ± s.e.: −2.30 ± 0.27 vs. −4.40 ± 0.35 and −3.79 ± 0.25), but this was not the case for the additional drug-induced weight loss (Table 2). The improvements in HbA1c, might suggest reduced urinary energy losses from glycosuria which could explain the lower weight loss (23).

This positive finding of a greater dose-dependent decrease in HbA1c in both active treatment groups in comparison with placebo (despite HbA1c measurements at baseline that were only ∼7.5%) is striking and would support the concept that CB1 receptor antagonists may have effects on glycemic control over and above weight loss (12).

Unwanted side effects of CP-945,598 were in keeping with class effects for CB1 antagonists. The incidence of nausea and diarrhea occurred more frequently in the CP-945,598 treatment groups than in the placebo groups, and the incidence of these AEs was also dose-related across all three studies. There was an increase in the incidence of depression and depressed mood in the patients taking the drug in comparison with those on placebo, but the incidences did not appear to be dose-dependent (DM-1022: 7.9% and 7.5% vs. 4.5%; MN-1019: 4.7% and 4.1% vs. 3.3%; NA-1025: 3.6% and 3.4% vs. 1.8% for the 10-mg and 20-mg CP-945,598 groups vs. placebo). However, the self reported experiences of psychological effects provided mixed evidence. For example, the proportion of participants who admitted to suicidal thoughts on at least one occasion (item 9 of PHQ-9) were higher for CP-945,598 than for placebo, and there was a dose-dependent effect of this trend in two of the three studies (DM-1022: 3.9% and 4.9% vs. 3.7%; MN-1019: 3.2% and 4.0% vs. 0.8% for the 10-mg and 20-mg CP-945,598 groups vs. placebo).

Despite weight loss, weight-loss maintenance, and biochemical improvement, the difficulties of developing antiobesity drugs that are effective, have an acceptable side effect and safety profile, and can meet regulatory hurdles are clearly highlighted by these studies.

The decision to discontinue these studies and the CP-945,598 development program in November 2008, was based on changing regulatory perspectives of the risk/benefit profile of CB1 receptor-related drugs, and the resulting new regulatory requirements for approval. At this time, all ongoing study participants had reached at least 12 months of treatment exposure. However, this decision terminated study participation at various time points beyond 12 months for studies MN-1019 and NA-1025. Such an early termination clearly alters the reliability of statistical analyses after the first year of treatment.

In conclusion, CP-945,598 resulted in a dose-related mean percentage reduction from baseline in body weight after 1 year of treatment in the FAS population of diabetic and nondiabetic participants: 10-mg CP-945,598: −4.76, −7.30, and −6.98; 20-mg CP-945,598: −6.21, −8.05, and −8.04; and placebo: −2.80, −5.62, and −5.33 for DM-1022, MN-1019, and NA-1025, respectively.

Just over 40% of the nondiabetic FAS (LOCF) populations on active treatment in MN-1019 and NA-1025 achieved a 5% weight loss at 1 year. A third of the diabetic participants in the DM-1022 study achieved a 5% reduction in body weight during this time. The proportion was even higher in participants who remained compliant during the trials. A greater number of participants also achieved at least 10% weight loss on active treatment than placebo in all three trials.

Discontinuations and some of the commonly reported AEs (diarrhea, nausea, nasopharyngitis, and headache) occurred more frequently in participants on active treatment compared with those on placebo. Self-reported experiences of psychological symptoms (anxiety and suicidal thoughts) were generally higher in the treatment groups than placebo, but not always in a dose-dependent manner. The incidence of depression and depressed mood was more commonly reported in participants on active drug than on placebo in all three trials, but was similar between the 10-mg and 20-mg CP-945,598 treatment groups within each trial.

In participants with mainly well-controlled type 2 diabetes, the combined effects of lifestyle and CP-945,598 induced substantial improvements in glycemic control.

Acknowledgmant

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgmant
  8. DISCLOSURE
  9. REFERENCES

These studies were funded by Pfizer Editorial support was provided by Brenda Smith, PhD, and Fiona Nitsche, PhD, of UBC Scientific Solutions and funded by Pfizer.

DISCLOSURE

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgmant
  8. DISCLOSURE
  9. REFERENCES

L.J.A. discloses the following relationships: Arena—research support. Amylin—advisor, research support. Cardiometabolic Support Network—shareholder. GI Dynamics—advisor. GlaxoSmithKline—advisor. Merck—advisor. Metabolic Therapeutics—consultant. Neurosearch—advisor. Orexigen—advisor, research support. Pfizer—advisor, research support. Metabalous Pharmaceuticals—patents, shareholder. Transtech—advisor, research support. Vivus—advisor, research support. N.F. has received research funding and provided paid medical consultancy to Janssen-Cilag, Merck, sanofi-aventis, and Abbott Laboratories. He was an investigator in the multicenter trial sponsored by Pfizer presented in this article. P.A.H. has worked on Advisory Boards and received Honoraria from Novo Nordisk, Roche, Pfizer, BMS, Orexigen, and sanofi-aventis. She was an investigator in the multicenter trial sponsored by Pfizer presented in this article. R.D.E., S.S.K., R.D.C., R.J.F., C.M.P., and J.D.O. are all employees of Pfizer, own Pfizer stock, and have Pfizer stock options.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgmant
  8. DISCLOSURE
  9. REFERENCES
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