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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Objective

Raynaud's phenomenon (RP) affects 3–9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX-503, in the treatment of RP in an ambulatory setting.

Methods

We conducted a multicenter, randomized, placebo-controlled study with a 2-week single-blind run-in period to determine baseline severity, followed by a 4-week double-blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX-503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0–10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run-in period in terms of ambient temperature) compared with baseline.

Results

The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX-503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX-503 had a side effect profile similar to that of placebo.

Conclusion

MQX-503 is well tolerated and more effective than placebo for the treatment of RP.

Raynaud's phenomenon (RP) is a common disorder characterized by cold-induced vasospasm of the digital arteries, resulting in decreased perfusion of the distal extremities. Primary RP, which is not associated with an underlying connective tissue disease, affects up to 9% of women and 6% of men in the US (1). More than 90% of patients with systemic sclerosis (SSc) experience secondary RP (2). Disease is often more severe in these patients, and digital ulcers due to fibrosis and luminal narrowing of the digital arteries can develop (3). RP often leads to substantial disability, and the current treatment options are not optimal (4).

Because of the vasodilating properties of nitrates, they have been used for decades for the treatment of primary and secondary RP. Several formulations, including ointments (5–7), sublingual tablets (8), tape (9, 10), and transdermal patches (11), have been shown to improve finger temperature or perfusion in patients with primary or secondary RP. However, these studies have shown a high frequency of side effects in treated patients, in particular headaches, dizziness, and skin irritation (5–7, 11).

MQX-503 is a novel preparation of topical nitroglycerin gel that absorbs quickly and promotes local vasodilatation. This formulation (nitroglycerine USP or 10% nitroglycerine in propylene glycol), which is a microemulsion of ∼50% lecithin-based organic phase and 50% water phase, has a rapid onset of action, as demonstrated by animal and human studies. MQX-503 has been shown to increase auricular artery blood flow by 1.4–4.0-fold of the baseline level within 5 minutes of application to the ears of NZW rabbits (Richmond K: unpublished observations). A laboratory-based randomized, placebo-controlled study in 37 patients with primary or secondary RP showed that MQX-503 was well tolerated and led to a significant improvement in blood flow (12). In that study, patients applied 0.5% MQX-503, 1.25% MQX-503, or placebo gel to their fingers immediately prior to a cold challenge. Finger blood flow was measured by laser Doppler imaging at baseline and at multiple time points after the cold challenge, to determine the time required for a return to baseline blood flow. Improvements in blood flow were evident as early as 5 minutes after the cold challenge in the MQX-503 groups. The mean time required to achieve baseline blood flow was significantly shorter in the 2 active-treatment groups compared with the placebo group, with no significant dose-response effect. In both animal and humans studies, no clinically significant changes in systolic or diastolic blood pressure occurred with MQX-503 treatment, which is consistent with the local activity of this formulation.

The purpose of the current study was to evaluate the tolerability and efficacy of MQX-503 in the treatment of RP in an “in-life” study.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Design overview.

This was a multicenter, randomized, placebo-controlled study consisting of 3 phases: a 2-week single-blind placebo run-in period, a 4-week double-blind treatment period, and a 1-week followup period. After the screening evaluation, which could occur up to 30 days prior to the first run-in visit, study visits took place on a weekly basis. Vasodilator medications, including calcium-channel blockers, α-adrenergic inhibitors, and other forms of nitroglycerin, were discontinued for at least 14 days prior to the run-in period. Patients were enrolled from January 2006 through the beginning of April 2006, and all study visits were completed by late May 2006.

Setting and participants.

Outpatients with a clinical diagnosis of RP, either primary or secondary to a connective tissue disease, were enrolled at 18 clinical centers throughout the US and Canada. Approval from the local or independent commercial institutional review board of each participating center was obtained prior to the study initiation. The study was conducted in accordance with the Declaration of Helsinki, and all patients provided written informed consent prior to undergoing any study procedures. The diagnosis of RP was based on a history of cold sensitivity with pallor or cyanosis of the digits, or an event observed by the study physician. Fulfillment of the American College of Rheumatology classification criteria for the diagnosis of SSc (13) and other connective tissue diseases was based on the assessment of the investigators, all of whom are members of the Scleroderma Clinical Trials Consortium.

Men and women between the ages of 18 years and 70 years were eligible for the study. Women of childbearing potential were required to have negative results of a pregnancy test at the screening evaluation and to use effective contraception throughout the study.

Exclusion criteria included the following: concurrent use of any form of nitrate therapy or medications that interact with nitroglycerin, such as phosphodiesterase V inhibitors; a known allergy to nitroglycerin or common topical gel ingredients; a history of migraine, cluster headaches, or vascular headaches; a history of myocardial infarction, uncontrolled congestive heart failure, unstable angina, or uncontrolled blood pressure within the preceding 3 months; the presence of nonepithelialized skin lesions on the dorsal aspects or sides of the fingers where the gel would be applied; and any medical condition that, in the judgment of the investigator, would interfere with study evaluations or procedures.

Randomization and interventions.

Patients who experienced at least 5 RP episodes in a 7-day period during the placebo run-in phase, as determined by electronic diary review, were randomly assigned to receive either placebo or 0.9% study gel for the 4-week treatment phase. This dose of MQX-503 was selected as a mid-range dose between the 2 doses used in the laboratory-based study (12). Randomization (1:1 ratio) to MQX-503 or placebo was performed, and patients and investigators were blinded to the study group allocation. Study medication was supplied in individual-dose Del Pouch applicators (Catalent Pharma Solutions, Somerset, NJ) with 0.5 gm of gel. Patients were instructed to apply the contents of 1 gel pouch immediately before or up to 5 minutes after the onset of an RP event, with a maximum of 4 applications daily and at least 2 hours between each application. Gel was to be applied to the dorsal aspects and sides of all affected fingers over a period of 1 minute.

Outcomes and followup.

Throughout the study, patients used an electronic diary to record each gel application and/or RP event, including the onset time, the duration of the episode, and the severity of pain, numbness, and tingling associated with the event. At the end of each day, patients recorded the number of additional RP episodes experienced over the preceding 24 hours that they had not previously recorded throughout the day. Patients also recorded a daily Raynaud's Condition Score (RCS), a validated composite self-assessment of the severity of RP encompassing the number and duration of episodes, the associated symptoms, such as pain and numbness, and the degree of hand disability (4). The RCS was recorded using a visual analog scale (VAS) from 0 (no difficulty with RP) to 10 (extreme difficulty with RP). The electronic diaries were programmed to emit an alarm every evening to remind patients to complete their daily report forms.

At each followup visit, adverse events and concomitant medications were reviewed. Each week patients completed 3 VAS questionnaires (range 0–100) assessing the severity of their RP, their overall health, and the severity of headaches associated with gel application experienced over the preceding week. Physicians also completed 2 VAS questionnaires rating the severity of the patients' RP and overall systemic disease for the past week.

A complete physical examination with blood pressure and laboratory studies, including a urine pregnancy test in women of childbearing potential, was performed at the time of screening and at completion of the treatment phase. For patients with SSc, the number of digital ulcers at permitted areas (i.e., the tips of digits) was recorded at the screening visit and at the first and last treatment visits.

Statistical analysis.

The baseline characteristics between treatment groups were compared using Student's t-tests for continuous variables and the chi-square or Fisher's exact test for categorical variables. All statistical tests were 2-sided. P values less than 0.05 were considered significant.

Sample size calculations were based on the assumption of detecting at least a 20% difference in the proportion of patients with a 30% improvement in the RCS in the MQX-503 group versus the placebo group. Assuming an alpha level of 0.05 and an underlying 2-sided binomial distribution, 200 patients randomized in a 1:1 manner to each treatment group provided the study with 90% power to detect a difference between the treatments.

Efficacy analyses were performed for the intent-to-treat (ITT) population, comprised of all randomized patients who had applied at least 1 dose of the study drug and had recorded data in their electronic diaries. Only observed data were used, and no imputation was performed. The primary efficacy outcome was the change in the mean daily RCS at the target week compared with baseline. The baseline RCS was calculated as the average daily RCS during the 2-week placebo run-in phase. The target week was defined as the week during the treatment phase that most closely matched the run-in period in terms of ambient temperature, as verified by weather stations near each clinic site. Target weeks were determined for each patient at each site prior to unblinding of the study. Comparisons of the mean daily RCS within groups from the target week to baseline were performed using the paired t-test. Comparisons between groups were performed using the 2-sample t-test. Subgroup analyses were also performed for patients with SSc, secondary RP, and primary RP.

To verify the results, a post hoc repeated-measures mixed model analysis was conducted, with patient as random factor, treatment and visit as fixed effects, change in ambient temperature as a covariate, and an interaction term for treatment by change in ambient temperature. Secondary outcome measures included the change in the mean number and duration of RP events and the change in the weekly patient- and physician-reported VAS scores during the target week compared with baseline. For patients with SSc, the proportion of patients with new digital ulcers during the study was determined. Chi-square tests were performed to compare proportions between the treatment groups.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Disposition of patients.

Figure 1 shows the disposition of patients. A total of 290 patients completed screening evaluations. After the run-in period, 219 (76%) of the patients screened were eligible for randomization and were included in the ITT analyses. One hundred eight patients were randomly assigned to receive placebo, and 111 patients were assigned to receive MQX-503. Of the 219 patients randomized, 212 (97%) completed the study. Of the 7 patients who discontinued treatment, 2 patients discontinued because of an unsatisfactory response, 3 discontinued because of adverse events, and 2 discontinued because of the use of an unacceptable concomitant medication.

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Figure 1. Patient disposition.

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Compliance with the protocol.

Ninety-four percent of randomized patients completed the study without any major protocol violation. In the ITT population, the mean number of gel applications per week during the treatment phase was similar in the MQX-503 and placebo groups (8.95 versus 9.26 applications per week).

Demographic characteristics.

Demographic characteristics were generally similar in the MQX-503 and placebo groups (Table 1). The majority of patients were female, and the most common racial background was non-Hispanic white in both treatment groups. The mean age of patients was ∼46 years in both groups. There were more smokers in the MQX-503 group compared with the placebo group (9 versus 2). Sixty-nine patients (32%) had primary RP, and 150 (68%) had RP secondary to an underlying disease. Sixty-seven patients (60%) in the treatment group and 64 (59%) in the placebo group had RP secondary to SSc. Calcium-channel blockers had been used at some time in the past by 50 patients (45%) in the MQX-503 group and 54 patients (50%) in the placebo group, with 21 patients in each group discontinuing the medication 2 weeks prior to the run-in period.

Table 1. Demographic characteristics of the patients at baseline*
CharacteristicMQX-503 (n = 111)Placebo (n = 108)
  • *

    Except where indicated otherwise, values are the number (%). SSc = systemic sclerosis; CCB = calcium-channel blocker.

  • Other causes of secondary Raynaud's phenomenon (RP) included systemic lupus erythematosus, undifferentiated connective tissue disease, mixed connective tissue disease, rheumatoid arthritis, Sjögren's syndrome, hypothyroidism, and fibromyalgia.

Female sex101 (91)102 (94)
Race  
 Non-Hispanic white92 (83)87 (81)
 Black8 (7)7 (6)
 Hispanic7 (6)4 (4)
 Asian/Pacific Islander3 (3)5 (5)
 Other1 (1)5 (5)
Age, mean ± SD years45.5 ± 11.746.4 ± 11.1
Smoker9 (8)2 (2)
Primary RP32 (29)37 (34)
Secondary RP79 (71)71 (66)
 SSc67 (60)64 (59)
 Other12 (11)7 (7)
Past CCB use50 (45)54 (50)

Raynaud's Condition Score.

At baseline, the mean ± SD RCS for patients receiving MQX-503 was similar to that for patients receiving placebo (3.34 ± 2.07 versus 3.18 ± 1.93; P > 0.20). Patients treated with MQX-503 experienced a significant improvement in the RCS of 0.48 (14.3%) during the target week compared with baseline (P < 0.001) (Figure 2). Patients receiving placebo had a statistically nonsignificant improvement in the RCS of 0.04 (1.3%). The change from baseline in the mean RCS was significantly greater in the MQX-503 group compared with the placebo group (P = 0.04). A repeated-measures analysis of covariance model that accounted for ambient temperature variations showed that both MQX-503 treatment and change in ambient temperature had significant effects (Table 2). The estimated least squares mean difference between MQX-503 and placebo was −0.37 (P = 0.04).

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Figure 2. Percent change in the mean Raynaud's Condition Score (RCS) at the target week compared with baseline in patients treated with MQX-503 or placebo. ∗ = P < 0.001 versus baseline; ∗∗ = P = 0.79 versus baseline; ∗∗∗ = P = 0.04.

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Table 2. Repeated-measures analysis of covariance model
EffectNumerator, dfDenominator, dfF valueP, Pr > F value
MQX-503 treatment12147.290.008
Visit32141.270.29
Change in ambient temperature121418.67<0.0001
Treatment by change in ambient temperature interaction12143.280.07

Frequency of RP events.

The mean ± SD number of daily RP events was 2.80 ± 1.81 in the MQX-503 group and 2.81 ± 1.76 in the placebo group at baseline (P > 0.20). At the target week, the mean number of episodes decreased by 0.73 episodes per day in the treatment group, compared with 0.54 episodes per day in the placebo group (P = 0.19).

Duration of RP events.

The mean ± SD duration of RP events at baseline was 28.8 ± 12.9 minutes in the MQX-503 group and 29.8 ± 13.6 minutes in the placebo group (P > 0.20). There was no significant decrease in the duration of events in either group at the target week.

VAS scores.

Changes in weekly patient- and physician-reported VAS scores at the target week compared with baseline were similar in the treatment and placebo groups (data not shown).

Subgroup analyses according to RP subtype.

MQX-503 treatment improved the mean RCS in patients with SSc, secondary RP, and primary RP by 12.3 (−0.38%), 15.0 (−0.50%), and 21.3 (−0.77%), respectively, at the target week compared with baseline (Figure 3). In contrast, placebo treatment resulted in only a 6.0 (−0.22%) improvement in the RCS in patients with primary RP (P = 0.26, MQX-503 versus placebo), no change in patients with SSc (P = 0.11, MQX-503 versus placebo), and worsening of the RCS by −4.4 (0.12%) in patients with secondary RP (P = 0.02, MQX-503 versus placebo). The proportion of SSc patients with new digital ulcers during the study was similar in the MQX-503 and placebo groups (9% versus 13%; P = 0.51).

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Figure 3. Percent change in the mean Raynaud's Condition Score (RCS) at the target week compared with baseline in patients treated with MQX-503 or placebo, according to the subtype of Raynaud's phenomenon.

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Safety.

At least 1 adverse event was reported by 79 (71%) of the patients receiving MQX-503 and by 71 (66%) of the patients receiving placebo (P = 0.39) (Table 3). Three serious adverse events occurred during the course of the study, but none was considered to be related to the study medication. One patient in the MQX-503 group, who had a history of mixed connective tissue disease, was hospitalized for a possible pulmonary embolus after a period of immobility. She was subsequently rehospitalized for pneumonia possibly related to immunosuppression with methotrexate. One patient in the placebo group was involved in a serious motor vehicle accident requiring admission to the intensive care unit.

Table 3. Adverse events occurring in at least 3% of patients*
 MQX-503 (n = 111)Placebo (n = 108)
  • *

    Values are the number (%).

Total adverse events79 (71)71 (66)
Headache25 (23)23 (21)
Upper respiratory tract infection12 (11)11 (10)
Dizziness11 (10)8 (7)
Nausea4 (4)6 (6)
Seasonal allergy5 (5)3 (3)
Sinusitis5 (5)3 (3)
Arthralgia5 (5)1 (1)
Gastroesophageal reflux5 (5)1 (1)
Skin ulcer4 (4)4 (4)
Pruritus4 (4)3 (3)
Skin irritation3 (3)4 (4)
Fatigue3 (3)2 (2)
Nasopharyngitis2 (2)3 (3)
Paresthesia2 (2)3 (3)
Dry skin3 (3)1 (1)
Hypokalemia0 (0)3 (3)

Overall, the numbers of adverse events were not statistically different between the groups. In particular, 25 patients (23%) in the MQX-503 group and 23 patients (21%) in the placebo group experienced headaches during the study. Likewise, 11 patients (10%) in the MQX-503 and 8 patients (7%) in the placebo group reported dizziness. Three patients (3%) in the treatment group and 4 patients (4%) in the placebo group experienced skin irritation at the treatment site. At the time of screening, the mean ± SD systolic and diastolic blood pressures were similar in the treatment group (118.5 ± 14.5 mm Hg and 72.6 ± 8.7 mm Hg, respectively) and the placebo group (117.5 ± 13.9 mm Hg and 72.4 ± 10.2 mm Hg, respectively). Values remained stable at study termination in both groups (119.5 ± 16.3 mm Hg and 71.6 ± 10.0 mm Hg, respectively, in the MQX-503 group; 117.8 ± 16.5 mm Hg and 71.6 ± 10.6 mm Hg, respectively, in the placebo group), and there was no significant difference in the change in mean blood pressure between the groups.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

This study is the largest placebo-controlled study evaluating a topical nitrate for the treatment of RP in an ambulatory setting. We demonstrated that MQX-503 was well tolerated and reduced the severity of RP, as measured by the RCS. Patients with primary RP treated with MQX-503 experienced a greater percent improvement in the RCS than those with SSc; these patients also experienced a positive placebo effect. This is not unexpected, given the underlying structural disease affecting the digital arteries of patients with SSc. We did not observe a significant improvement in the number of RP episodes in the treatment group compared with the placebo group. It is possible that our study design, in which patients were instructed to apply the medication only if they anticipated or were having an episode rather than at scheduled intervals for prevention, affected the potential impact of MQX-503 on the rate of RP episodes.

MQX-503 is a microemulsion formulation of topical nitroglycerin gel with a proprietary surfactant system designed for rapid, nonirritating, local delivery of the active agent. Hummers et al reported that when MQX-503 was applied to the fingers, it induced local vasodilatation of the digital arteries without significant decreases in systolic or diastolic blood pressure (12). This contrasts with other formulations of nitroglycerin such as glycerol trinitrate ointment (5, 6) and nitroglycerine tape (10). In our study, the proportion of patients who experienced headaches and dizziness was similar in the MQX-503 group and the placebo group. Studies of other formulations of nitroglycerin demonstrated a high incidence of these side effects (5, 14), with headaches reported in >80% of patients in one study (11). In our study, skin irritation was also reported equally in the MQX-503 and placebo groups in only a few patients, suggesting tolerability of the topical vehicle.

Previous studies of nitroglycerin for the treatment of RP have predominantly been small, laboratory-based studies evaluating changes in blood flow using venous occlusion plethysmography (6) or laser Doppler imaging (7, 15), or changes in finger temperature using thermography (9, 10). Only 2 small double-blind placebo-controlled studies have evaluated the effects of nitroglycerin ointment or patches on the frequency and severity of RP events (5, 11). These trials showed a reduction in the number and severity of RP episodes in patients treated with the active medications. However, these 2 studies, as well as other trials evaluating calcium-channel blockers, α-adrenergic inhibitors, and selective serotonin reuptake inhibitors, did not use the RCS, a now accepted and valid measure of severity of RP (5, 11, 16–20). In addition, most previous studies used paper diaries rather than electronic diaries that prompted patients to input their daily RCS. Compliance with electronic diaries has been reported to be 94% compared with only 11% compliance with paper diaries (21).

Previous studies of systemic vasodilating agents for the treatment of RP show an effect on the RCS similar to that observed with MQX-503. Compared with placebo, treatment with the intravenous form of the prostacyclin analog, iloprost, resulted in a 15% improvement in the RCS in patients with SSc (22). Although effective, treatment with intravenous iloprost resulted in headaches in 84% of patients and flushing in 50% of patients treated with the active medication (22). In addition, the oral formulation of iloprost did not show a benefit over placebo in the treatment of RP (23). Phosphodiesterase V inhibition may be useful for the treatment of RP, but further studies are necessary (24, 25). Treatment with sildenafil was shown to improve the RCS by 27% compared with placebo in a small crossover study of 18 patients (16 with secondary RP and 2 with primary RP) (25). However, tadalafil had no effect on digital blood flow or cold-induced vasoconstriction in patients with primary RP (26) and no significant clinical benefit over placebo in patients with SSc-associated RP (27).

Our study had several limitations. First, we used a parallel study design that was not able to control for the heterogeneity of our patient population with regard to the outcome measures. This may explain why we did not detect significant changes in the frequency and duration of episodes during the trial. Moreover, patient-perceived severity, as measured by the RCS, may be a better and more valid clinical measure than is episode frequency or duration, because some patients may have few severe episodes, and others may have many clinically mild events. It is possible that improvements in the RCS were in part related to the effects of nitroglycerin on pain modulation (28). The high degree of variability in the outcome measures in our study is likely attributable to the “in-life” design and the influence of daily events experienced by individual patients with RP. We plan to confirm our findings by performing a second study using a crossover design, thus allowing the comparison of individual patients and patient groups with each other.

The second limitation of our study is the influence of ambient temperature on the severity of RP (29, 30). Ambient temperature variability during the study period affects all trials of therapy for RP. In our study, the RCS was negatively correlated with ambient temperature, as would be expected (Pearson's correlation coefficient = −0.10, P = 0.007). We adjusted for this by making our primary outcome a comparison of baseline with a period of similar ambient temperature (i.e., the target week). Third, because dosing was on an as-needed basis, we were unable to determine the effects of MQX-503 on the prevention of RP episodes. Finally, there are no data to suggest what constitutes a minimal clinically important difference (MCID) in RCS scores. Although the study was initially powered to show a difference in the proportion of patients achieving a 30% reduction in the RCS, based on previous studies with calcium-channel blockers (16), we nevertheless were able to show a statistically significant difference in the change in the mean RCS between the MQX-503 and placebo groups. Further studies will be required to define the MCID in RCS values.

Our study showed ∼13% improvement in the RCS in patients treated with MQX-503 compared with placebo. MQX-503 represents a novel topical alternative for the treatment of RP. It is well tolerated and may be useful for patients with either primary or secondary disease, with possibly greater effects in the former subgroup. The short half-life and local activity of the drug in this formulation allow for use on an as-needed basis, without systemic side effects. This study provides initial experience with MQX-503 in the ambulatory setting, demonstrating safety and improvement in the severity of RP. Future studies comparing MQX-503 with currently available nitroglycerin formulations or calcium-channel blockers will be informative in assessing the relative efficacy of this novel agent.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Dr. Chung had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Sule, Steen, Dechow.

Acquisition of data. Chung, Shapiro, Fiorentino, Baron, Shanahan, Sule, Hsu, Rothfield, Steen, Martin, Smith, Mayes, Simms, Pope, Kahaleh, Csuka, Gruber, Collier, Sweiss, Gibert, Dechow, Gregory, Wigley.

Analysis and interpretation of data. Chung, Martin, Mayes, Gilbert, Dechow, Gregory, Wigley.

Manuscript preparation. Chung, Shapiro, Fiorentino, Baron, Sule, Steen, Martin, Smith, Mayes, Simms, Pope, Dechow, Gregory, Wigley.

Statistical analysis. Chung, Gilbert.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

MediQuest Therapeutics provided the funding and study drug and contributed to the study design, collection of data, and data analysis for this study. The funding source and all authors approved of the final manuscript and agreed to submit the manuscript for publication.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

We thank Eric Batson, MD, PhD, and Melissa Nelson, PhD, for critically reviewing the manuscript and assisting with the data analysis.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
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