Trial Design

This was a randomized, multicentre, open-label, comparative, phase 3 clinical trial conducted at 12 sites in India in patients with CLBP, to evaluate the efficacy and safety of an FDC of pregabalin prolonged release (75 mg) and etoricoxib (60 mg) in comparison to etoricoxib (60 mg) alone.

The study was scheduled to have four visits: visit 1, screening visit (day − 14 to day − 1); visit 2, enrolment visit (day 0); visit 3, follow-up visit (day 28 ± 4); visit 4, end of study visit (day 56 ± 4). All the efficacy and safety assessments were conducted as per the schedule of assessments. The trial design is illustrated in Fig. 3.

Fig. 3

The clinical trial was registered with the clinical trials registry of India (CTRI; CTRI/2018/10/015886).

The trial was initiated after obtaining regulatory and ethics committee approval and was conducted in accordance with the ethical principles of the Declaration of Helsinki, approved study protocol and applicable regulatory requirements. All patients signed informed consent prior to any study-related procedure being performed.

Study Participants

Patients of either sex between 18 and 65 years of age suffering with CLBP and willing to comply with study procedures were included after obtaining written informed consent.

Male and non-pregnant, non-lactating female patients aged between 18 and 65 years (both inclusive) suffering from CLBP (symptoms duration at least 3 months) and having at least one of the following five features on the side corresponding to leg pain were considered eligible for participation in the study: (a) sharp and shooting pain below the knee; (b) pain evoked by straight leg raising to 60° or less; (c) decreased or absent ankle reflex; (d) weakness of muscles below the knee; (e) sensory loss in L5/S1 distribution, with a pain score of at least 4 on the numeric rating scale (NRS), without any critical illness or medical conditions .

A complete list of inclusion and exclusion criteria is given in the supplementary material.

Interventions

Enrolled patients were assigned randomly in a 1:1 ratio to receive either the FDC of low-dose pregabalin prolonged release 75 mg and etoricoxib 60 mg tablets (Emaxgalin, manufactured by Sun Pharma Laboratories Limited, Mumbai, India) (test) or etoricoxib 60 mg tablets (comparator) once a day with or without food. Randomization schedule was generated centre-wise by the sponsor using SAS Proc Plan (version 9.1.3 or higher). Permutated block size with undisclosed seed number was considered to maintain equal numbers of patients across centres. The randomization number was unique to each patient.

In case of intolerable CLBP, paracetamol 500 mg every 6–8 h was allowed to be used as rescue medication with total daily dose not exceeding 2 g.

Sample Size

The primary efficacy endpoint was used as the basis for sample size estimation. The sample size of 108 patients per group was required to detect a mean difference of 5 mm at 80% power and significance level set at 5%. Although the visual analogue scale (VAS) was used for estimation, given the high correlation between the VAS and NRS, it was assumed that the sample size calculated on the basis of VAS would be adequate to detect a difference in NRS as well. The common standard deviation was assumed to be 13 mm. In order to account for a 20% attrition in an 8-week study, 136 patients needed to be enrolled in each arm.

Outcome Measures and Endpoints

The primary efficacy outcome measure was assessment of mean change in the NRS from enrolment to 8 weeks.

The secondary efficacy outcome measures were (a) mean change in NRS from enrolment to 4 weeks, (b) mean change in Roland–Morris disability questionnaire (RDQ) from enrolment to 4 and 8 weeks, (c) mean change in VAS from enrolment to 4 and 8 weeks, (d) patient’s global impression of improvement (PGI-I) assessment at week 4 and 8, (e) clinical global impression of improvement (CGI-I) assessment at week 4 and 8 and (f) consumption of rescue medication (total dose of paracetamol tablets consumed) at week 4 and 8.

The safety outcome was the proportion of participants with adverse events (AEs) and serious adverse events throughout the study.

At the baseline visit, demographic information such as gender, age, height, weight, body mass index (BMI) and measurements pertaining to pain such as NRS, VAS, RDQ, PGI-I and CGI-I were recorded. All the efficacy outcome measures were recorded during the treatment period. Data pertaining to AEs and concomitant medications were recorded during the study.

The following scales were used to measure efficacy endpoints for the study.

Primary Outcome MeasuresNumeric Rating Scale

NRS is an 11-point scale that is widely used clinically for the assessment of pain [11]. Patients were asked to rate their pain from 0 to 10 on the following 11-point scale (a lower rating suggests improvement in back pain): 0 = no pain, 1–3 = mild pain, 4–6 = moderate pain, 7–10 = worst/severe pain. For patients with CLBP, a minimum clinically important change (MCIC) score is considered as 2.5 [12]. Assessments were performed at enrolment, week 4 and week 8.

Secondary Outcome MeasuresRoland–Morris Disability Questionnaire

RDQ is a commonly used patient-reported quality of life (QoL) questionnaire that assesses pain-related functional status. The RDQ consists of 24 statements relating to the person’s perceptions of their back pain and associated disability; 15 of these are related to physical ability/activity, three to sleep/rest, two to psychological aspects, two to household management, one to eating/diet and one to pain frequency [13]. Reduction in the RDQ score suggests improvement in functional status. It is recommended to consider a score of at least 3.5 as the MCIC [12]. Assessments were performed at enrolment, week 4 and week 8.

Visual Analogue Scale

VAS is the optimal tool for self-reporting of pain severity or intensity. It is usually presented as a 100-mm horizontal line on which the patient’s pain intensity is represented by a point between the extremes of ‘no pain at all’ (0 mm) and ‘worst pain imaginable’ (100 mm) [14]. The MCIC for VAS is 20 mm [12]. Assessments were performed at enrolment, week 4 and week 8.

Patient Global Impression of Improvement

As the name suggests, PGI-I is a global index used to rate the patients’ impression of their condition’s response to a particular therapy [15]. The assessment is based on the following ratings: 1 = very much better, 2 = much better, 3 = a little better, 4 = no change, 5 = a little worse, 6 = much worse, 7 = very much worse. Assessments were performed at week 4 and week 8.

Clinical Global Impression of Improvement

The CGI-I was developed to provide the clinicians’ assessment of patients’ global functioning before and after treatment [16]. The ratings are as follows: 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 7 = very much worse. Assessments were performed at week 4 and week 8.

Safety

Safety assessment was based on monitoring and recording of all AEs and serious adverse events, if any, and regular monitoring of hematology, renal function tests, liver chemistry test, urine pregnancy test, urine analysis and electrocardiogram. Measurement of vital signs was performed on every scheduled visit.

Data Collection

All data relating to the study were documented in the case report form. Data collection and documentation were performed as per International Council for Harmonisation Good Clinical Practice guidelines.

Statistical Methods

Efficacy was assessed in the intention-to-treat (ITT) population. Descriptive statistics for continuous and ordinal variables were presented as mean ± standard deviation or percentage, as appropriate. Categorical variables like gender and AEs were summarized using count and percentage. Demographic characteristics (gender, age, height, weight and BMI) between the two treatment groups were analyzed using Fisher’s exact test and Wilcoxon Mann–Whitney test.

Change in the NRS, RDQ and VAS values at 4 and 8 weeks from baseline was summarized as mean ± SD. The mean change between groups was compared using the Wilcoxon Mann–Whitney test, whereas the mean change within groups was compared using Wilcoxon signed rank test.

All statistical tests were performed using SAS version 9.1.3, USA. Unless otherwise specified, all the statistical analyses were performed at a two-sided 5% level of significance.