Trial design
This was a unicenter, balanced 1:1 randomized double-blind, placebo-controlled clinical trial, with a parallel design, conducted at the National obesity center, Cameroon.
Participants
Twenty-two participants with painful symmetrical diabetic neuropathy were recruited for this study, and were randomized to receive either capsaicin or the placebo cream. All were patients with type 2 diabetes who had daily pain or painful paresthesias in a neuropathic or radiculopathic distribution, intensity between 4 and 7 on a visual analogic scale, interfering with daily activities, work or sleep for at least 3 months duration.
Excluded, were patients with;
- History of allergies to any capsaicin product
- Diabetic patients with other diagnosed etiology responsible for peripheral neuropathy such as hepatitis, AIDS, Nutritional deficiencies (folate, vitamin B12)
- Presence of open skin lesions at the site of application of the study medication
- Signs of infection on limbs or amputations
- Pregnant or lactating females
- Subjects with other topical medication at site of application of study cream.
- All eligible patients who did not give their signed informed consent to participate.
Intervention
The study took place at the National Obesity Center of the Yaoundé Central Hospital, from January to April 2018.
Painful peripheral neuropathy was diagnosed using the Douleur Neuropathique 4 criteria and the Toronto Neuropathy Score [8]. Hepatitis screens, and HIV serology was done to exclude these as causes of the neuropathy. At baseline, Laboratory tests, physical examinations, vital signs and anthropometric characteristics such as body weight, height, blood pressure and general characteristics including age, duration of diabetes, history of hypertension, pain characteristics (intensity, duration, associated symptoms, and effect on quality of life) and ongoing medications were recorded at the beginning of the study.
Outcomes
The Primary outcome/endpoint of the study was the reduction in the mean pain score from baseline, as assessed by the Visual analogic scale (0-10 points). (Figure 1)
The secondary outcome was the level of improvement in quality of life score after intervention. This was evaluated using the physician’s global evaluation Score (Table 1).
Sample size
The Whitley formula was used to calculate the sample size
Where P1 is the proportion of patients experiencing relief from capsaicin
P2 is the proportion of patients experiencing relief from a placebo
According to a study carried out by Rub Tandan et al on capsaicin efficacy and neuropathy,
P1= 73% or 0.73
P2= 21% or 0.21
From statistic tables, α was set at 5% and β at 20% to obtain a power of 80%, giving a value of 7.9. This gave a minimum sample size of 11 patients per group.
Randomization and blinding
Randomization was done using computer software, with a 1:1 varying blocking type to preserve internal validity. Thus, randomization divided the eligible candidates into two groups 1 and 2, equally. Generation of the random allocation sequence, enrollment of participants, and distribution of drug type to participants was done by different members of the study group. The study drugs were Capsaicin 0.075% gel and Miconazole cream, in identical no-label white tubes. Both drugs were dispensed to patient according to randomized group assignment. Participants applied either of the drugs topically on the feet 3 times daily. Evaluations of the patients including assessment of the pain severity, assessment of quality of life, vital signs and examination, and questioning regarding the adverse effects were performed at each of a 2-week follow-up visit. Compliance was assessed by direct questioning.
A data and safety monitoring board was setup and could decide to withdraw a study participant, if there was development of any serious harm as a result of the trial. At the end of the 8th week, the study was stopped. Equipoise was assured by making sure all investigators, participants and data analysts were blinded to the allocation. Only members of the data and safety monitoring board were aware of the subjects per allocated arm. The data and safety monitoring board was accessible by telephone to all participants throughout the study.
Statistical analysis
The student t test was used to compare means for continuous variables between both groups. Categorical variables were compared using the chi square test. The primary analysis was intention-to-treat and involved all patients who were randomly assigned. The efficacy endpoint was the change in mean bi-weekly pain score on the Visual analogic scale. Values were expressed as means with ranges, and numbers and percentages. Statistical significance was set for p ≤ 0.05