FULL DETAILS (Read-only)  -> Click Here to Create PDF for Current Dataset of Trial
CTRI Number  CTRI/2018/10/015886 [Registered on: 03/10/2018] Trial Registered Prospectively
Last Modified On: 04/09/2019
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Active Controlled Trial 
Public Title of Study   A clinical trial to study the efficacy and safety of combination drugs of Pregabalin Prolonged Release and Etoricoxib in comparison to single therapy of Etoricoxib in patients having chronic low back pain in India. 
Scientific Title of Study   A randomised, multi-centric, open label, comparative study to evaluate efficacy and safety of fixed dose combination of Pregabalin Prolonged Release and Etoricoxib in comparison to Etoricoxib alone in patients having chronic low back pain in India. 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
ICR/16/002, Version No. 4.0, Dated 27/MAR/2018  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
Modification(s)  
Name  Dr Shilpi Dhawan 
Designation  General Manager 
Affiliation  Sun Pharma Laboratories Limited (SPLL) 
Address  Sun Pharma Laboratories Limited, Sun House, Plot No. 201 B/1, Western Express Highway, Goregaon (E)

Mumbai
MAHARASHTRA
400063
India 
Phone  02243245299  
Fax  022243244343  
Email  shilpi.dhawan@sunpharma.com  
 
Details of Contact Person
Scientific Query  
Name  Dr Maulik Doshi 
Designation  Medical Monitor 
Affiliation  Sun Pharma Laboratories Limited (SPLL) 
Address  Sun Pharma laboratories Limited Tandalja

Vadodara
GUJARAT
390020
India 
Phone  02656612829  
Fax  02652354897  
Email  maulik.doshi@sunpharma.com  
 
Details of Contact Person
Public Query  
Name  Guruprasad Palekar 
Designation  Operational Manager 
Affiliation  Sun Pharma Laboratories Limited (SPLL) 
Address  Sun Pharma Laboratories Limited Sun House, 201 B/1, Western Express Highway, Goregaon ( E)

Mumbai
MAHARASHTRA
400063
India 
Phone  02243245215  
Fax  02228947101  
Email  guruprasad.palekar@sunpharma.com  
 
Source of Monetary or Material Support  
Sun Pharma Laboratories Limited, Sun House,Plot No. 201 B/1, Western Express Highway, Goregaon ( E),Mumbai 400 063, Maharashtra, India  
 
Primary Sponsor  
Name  Sun Pharma Laboratories Limited 
Address  Sun House,Plot No. 201 B/1, Western Express Highway, Goregaon ( E),Mumbai 400 063, Maharashtra, India 
Type of Sponsor  Pharmaceutical industry-Indian 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study
Modification(s)  
No of Sites = 12  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Shrinivas Shankar Shintre  B. J. Government Medical College & Sassoon General Hospitals  Department of Orthopaedics, B. J. Government Medical College & Sassoon General Hospitals, Near Pune Railway Station, Pune-411001, Maharashtra, India
Pune
MAHARASHTRA 		 9822053186

drssshintre@gmail.com 
Dr Bhanoth Valya  Gandhi Hospital  In-Patient Block, Ground Floor, Ground Floor, Department Of Orthopaedics, Gandhi Hospital, Musheerabad, Secunderabad, Telangana - 500003
Hyderabad
TELANGANA 		 9000357799

orthovalya@gmail.com 
Dr Pawar Eknath Deosing  Grant Government Medical College and Sir J J group of Hospitals  Dept. of Orthopedic, Grant Government Medical College and Sir J J group of Hospitals, Byculla, Mumbai- 400008, Maharashtra, India
Mumbai
MAHARASHTRA 		 8551996777

eknathpawar999@gmail.com 
Dr Brijesh Patel  Hi-Tech Multispeciality Hospital  Hi-Tech Multispeciality Hospital, Sector 3-D, Plot No. 1180, Gh Road, Nr. Gh-11/2 Bus Stand, Gandhinagar, Gujarat - 382016
Gandhinagar
GUJARAT 		 9825686088

hitechhospital.cr@gmail.com 
Dr Rohit Patel  Kanoria Hospital & Research Centre  Kanoria Hospital & Research Centre, Airport-Gandhinagar Highway, Village- Bhat, Dist- Gandhinagar- 382428
Gandhinagar
GUJARAT 		 9898072682

kanoriacr@gmail.com 
Dr Ashish Kumar  King George’s Medical University  Department of Orthopaedic Surgery, King George’s Medical University, RALC Campus, Limb Centre, Nabi Ullah road, Lucknow (UP)-226018
Lucknow
UTTAR PRADESH 		 9415020202

drashish_kumar20202@yahoo.com 
Dr Selvakumar Chithambarakutalam Jayalekshmi  Kovai Diabetes Speciality Centre and Hospital  Kovai Diabetes Speciality Centre and Hospital, 15, Vivekananda Road, Ramnagar, Coimbatore – 641009, Tamil Nadu, India
Coimbatore
TAMIL NADU 		 98242275342

cjselvakumar@gmail.com 
Dr Vijay Goni  Nehru hospital  Department of Orthopaedics surgery, Nehru hospital, Postgraduate Institute of Medical Education & Research, Sector 12, Chandigarh 160012 India
Chandigarh
CHANDIGARH 		 9815712727

vijaygoni@gmail.com 
Dr G Sree Lakshmi  Osmania General Hospital  2nd Floor, QQ Building, Department of Neurology, Osmania General Hospital, Osmania Medical College, Afzalgunj, Hyderabad - 500012
Hyderabad
TELANGANA 		 9866193700

rangalakshmi@gmail.com 
Dr C L Nawal  SMS Hospital  G-1, Department of Medicine Dhanvantari OPD Block SMS Hospital, Jaipur- 302004
Jaipur
RAJASTHAN 		 9414053160

drclnawal@gmail.com 
Dr Ranajit Panigrahi  Sparsh Hospital and Critical Care Pvt. Ltd  Sparsh Hospital and Critical Care Pvt. Ltd, Plot No. A/407, Sahid Nagar, Bhubaneswar- 751007,Odisha
Khordha
ORISSA 		 9777037455

ranajitpanigrahi@gmail.com 
Dr Yeole Amit Bhalchandra  Supe Heart & Diabetes Hospital & Research Centre  Supe Heart & Diabetes Hospital & Research Centre, Opposite Adharashram, Gharpure Ghat, Near Rungtha High School, Ashok Stambh, Nasik-422002, Maharashtra, India
Nashik
MAHARASHTRA 		 9819651753

amit_yeole37@rediffmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 12  
Name of Committee  Approval Status 
Ethics Committee, S.M.S Medical College & Attached Hospitals  Approved 
HI-TECH ETHICS COMMITTEE (HEC)  Approved 
Institutional Ethics Committee Address Osmania Medical College  Approved 
Institutional Ethics Committee King George’s Medical University  Approved 
Institutional Ethics Committee of B. J. Govt. Medical College & Sassoon General Hospital  Approved 
Institutional Ethics Committee of Kovai Diabetes speciality centre & Hospital  Approved 
Institutional Ethics Committee Sparsh Hospital and Critical Care Pvt. Ltd  Approved 
Institutional Ethics Committee, Gandhi Medical College/Gandhi hospital  Approved 
Institutional Ethics Committee, Grant Government Medical College and Sir J J Group of Hospital  Approved 
Institutional Ethics Committee, Post Graduate Institute of Medical Education & Research  Approved 
Kanoria Ethics Committee  Approved 
Supe Hospital Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI
Modification(s)  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied
Modification(s)  
Health Type  Condition 
Patients  (1) ICD-10 Condition: G892||Chronic pain, not elsewhere classified,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Comparator Agent  Etoricoxib 60 mg tablet  One tablet once a day with or without food for 08 weeks 
Intervention  FDC Pregabalin prolonged release 75 mg and Etoricoxib 60 mg tablet  One tablet once a day with or without food for 08 weeks 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  65.00 Year(s)
Gender  Both 
Details  1.Male or female patients of 18 to 65 years of age (both inclusive)
2.Patients with chronic low back pain (symptoms duration: greater than or equal to 3 months) and at least one of the following features on the side corresponding to leg pain:
a.Sharp and shooting pain below the knee;
b.Pain evoked by straight leg raising to 60 degrees or less;
c.Decreased or absent ankle reflex;
d.Weakness of muscles below the knee.
e.Sensory loss in L5/S1 distribution
3.Patient who have pain score of at least 4 on a Numeric Rating Scale (11- point).
4.Patients who agree not to use any other approved or experimental pharmacological treatments for low back pain, other than mentioned in the protocol, at any time during the study.
5.Patient or his/her legally accepted representative is willing to give informed consent.
6.Female participants of childbearing potential must be willing to use acceptable method of contraception (female of childbearing potential is defined as one who has not been postmenopausal for at least one year, or has not been surgically sterilised, or has not had a hysterectomy at least three months prior to the start of this study. Acceptable method of contraception includes (e.g., barrier method with spermicide). The "calendar method," withdrawal, or an IUD is NOT an acceptable method.
7.Patients willing to follow the study protocol. 
 
ExclusionCriteria 
Details  1.Breast feeding or pregnant females
2.History of Hepatitis B, Hepatitis C or HIV infection
3.Anticonvulsants, antidepressants (eg tricyclic,tetracyclic,atypical),aspirin at doses greater than 81 mg/day,benzodiazepines,opioids,herbal medications,mexiletine HCl,epidural injection and procedure (eg acupuncture)performed within 6 weeks prior to screening or planning to use during the study or taken more than recommended doses of any dosage form of NSAIDs analgesics in last 15 days prior to screening and any treatment for low back pain within 2 days prior to enrolment
4.Patients who,in the opinion of the investigator,have history of clinically significant cardiovascular disease (ex MI),psychiatric disorders as per DSM-5 (Bipolar disorder,generalized anxiety disorder,depression,psychosis or post-traumatic stress disorder),epilepsy or seizure disorder requiring treatment with anti-epileptic drugs,severe hepatic and renal impairment(defined as either creatinine clearance less than 60 mL/min or renal dysfunction requiring hemodialysis),neoplastic disease, suicidal behavior,underlying conditions that may precipitate encephalopathy (ex liver failure),lactose intolerance,angle closure glaucoma,angioedema,urinary retention,thyroid disorder,uncontrolled hypertension and diabetes or abnormal ECG or the participant has any other abnormal laboratory value or MRI lumbosacral spine finding (eg neoplasia) of clinical significance for this study during screening visit
5.5. Medical condition or disorder that would interfere with the action, absorption, distribution, metabolism, or excretion of Pregabalin Prolonged Release or Etoricoxib in the investigators judgment
6.Patients with known alcohol or other substance abuse within last one year as per DSM-5 criteria
7.Participant has hypersensitivity, intolerance, or contraindication to the use of Etoricoxib and Pregabalin, or any of its components
8.HbA1c greater than 8% at screening
9.Patient received treatment with an investigational device or compound within 6 months prior of the screening.
10.Patients with clinically significant disorder that, in the opinion of the investigator, would result in the participant’s inability to understand and comply with the requirements of the study
11.Patients operating heavy complex machinery or who intend to drive

 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   An Open list of random numbers 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
Mean change in Numeric Rating Scale (NRS) from enrolment to 8 weeks   Mean change in Numeric Rating Scale (NRS) from enrolment to 8 weeks  
 
Secondary Outcome  
Outcome  TimePoints 
1.Mean Change in Numeric Rating Scale (NRS) from enrolment to 4 weeks
2.Mean change in Roland-Morris Disability Questionnaire (RDQ) from enrolment
3.Mean change in Visual Analogue Scale (VAS) from enrolment
4.Consumption of rescue medication (total dose of paracetamol tablets consumed)(post enrolment)
5.Patient Global Impression of Improvement (PGI-I)
6.Clinical Global Impression of Improvement (CGI-I)
7.Proportion of participants with adverse events and serious adverse events  		 1.04 weeks
2.04,08 weeks
3.04,08 weeks
4.04,08 weeks
5.04,08 weeks
6.04,08 weeks
7.08 weeks 
 
Target Sample Size   Total Sample Size="272"
Sample Size from India="272" 
Final Enrollment numbers achieved (Total)= "319"
Final Enrollment numbers achieved (India)="319" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)   10/10/2018 
Date of Study Completion (India) 01/04/2019 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Date Missing 
Estimated Duration of Trial   Years="2"
Months="6"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Not Applicable 
Recruitment Status of Trial (India)  Completed 
Publication Details   None 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Brief Summary
Modification(s)  		 This is a randomised, multi-centric, open label, parallel group, comparative phase III clinical study to evaluate efficacy and safety of fixed dose combination of Pregabalin prolonged release and Etoricoxib in comparison to  monotherapy of Etoricoxib  in patients having chronic low back pain. Male or female 272 subjects with age between 18 to 65 years, diagnosed with chronic low back pain for at least 03 months and NRS score of at least 4 will be enrolled in the study. Total study duration of 10 weeks will consist of 4 visits including: one screening visit, one enrolment visit, one follow-up visit and end of the study visit at 08 weeks. Efficacy analysis will be assessed by change in Numeric Rating Scale (NRS), Roland-Morris Disability questionnaire (RDQ), Visual Analog Scale (VAS), Patient Global Impression of Improvement (PGI-I) and Clinical Global Impression of Improvement (CHI-I) from baseline to 08 weeks.
2. Mean change in Roland-Morris Disability Questionnaire (RDQ) from enrollment [Time frame: 04, 08 weeks]
3. Mean change in Visual Analogue Scale (VAS) from enrollment [Time frame: 04, 08 weeks]
4. Consumption of rescue medication (total dose of paracetamol tablets consumed) (post enrolment) [Time frame: 04, 08 weeks]
5. Patient Global Impression of Improvement (PGI-I) [Time frame: 04, 08 weeks]
6. Clinical Global Impression of Improvement (CGI-I) [Time frame: 04, 08 weeks]
7. Proportion of participants with adverse events and serious adverse events [Time frame: 08 weeks]

Discussion and Conclusion:
This was a phase III, randomized, multi-centric, active controlled, parallel group, open-label,
comparative study conducted at 12 active sites in 319 patients to evaluate efficacy and safety of
FDC of Pregabalin Prolonged Release and Etoricoxib in comparison to Etoricoxib alone in patients having chronic low back pain. Eligible patients were randomized to either FDC of Pregabalin Prolonged Release and Etoricoxib or Etoricoxib arm and treatment of once daily was given for eight weeks. Efficacy was assessed by evaluating effect of treatment on pain intensity and functional status by validated scales. For pain intensity NRS and VAS were used whereas for functional status RDQ was used. Safety was assessed by profile of TEAEs.

Principal Findings:
This trial demonstrated that treatment with FDC of Pregabalin Prolonged Release and Etoricoxib had provided superior efficacy than Etoricoxib alone in primary outcome measures such as NRS as well as on secondary outcome measures such as RDQ, VAS, PGI-I and CGI-I. It is worthwhile to note that effect on all these parameters were seen as early as by 28 days. Use of rescue medication Paracetamol was less in test arm than Comparator arm. Both study medications were well tolerated and safe in study population.

Efficacy Data:
1. Effect on Pain Intensity Domain:
An NRS involves asking patients to rate the pain from 0 to 10 (an 11-point scale). Reduction in the scale suggests improvement in back pain. It is suggested that in chronic low back pain minimum clinically important change (MCIC) is 2.5. We have observed in our study that change from baseline at eight weeks was significantly higher (4) in FDC of Pregabalin Prolonged Release and Etoricoxib arm than both MCIC (2.5) and Etoricoxib arm (2.92). We have seen similar trend in assessment of VAS. In test arm change from baseline at eight weeks was significantly higher (37.6 mm) than both MCIC (15 mm) and Comparator arm (28.5 mm). Thus, we can say that our test arm FDC of Pregabalin Prolonged Release and Etoricoxib has demonstrated both clinically and statistically significant reduction in NRS and VAS scores both than comparator arm.

2. Effect on Functional Status Domain:

Low back pain interferes with activities such as mobility, dressing, sitting and standing. Patients can give this information by completing disability questionnaires such as Roland–Morris Disability Questionnaire (RDQ). The RDQ focuses on a limited range of physical functions, including walking, bending over, sitting, lying down, dressing, sleeping, self-care and daily activities. The MCIC of the RDQ has been assessed in a number of studies. It is recommended to consider at least 3.5 as MCIC. We have observed that in test arm change from baseline at eight weeks was significantly higher (9.28) than both MCIC (3.5) and Comparator arm (6.78). Thus, our test arm FDC of Pregabalin Prolonged Release and Etoricoxib has demonstrated both clinically and statistically significant reduction in RDQ scale than comparator arm.

 

Improvement in NRS, VAS and RDQ can be reflected very well in other secondary outcome parameters such as PGI-I, CGI-I and consumption of rescue medication Paracetamol. Thus we can say that FDC of Pregabalin Prolonged Release and Etoricoxib has demonstrated both clinically and statistically significant effect than comparator arm Etoricoxib alone.

Safety Data: 

We have observed that a total of 19 patients had atleast one TEAE. Total number of TEAEs in
our study were 22. Incidence of TEAEs were 11 (6.9%) in test arm and 8 (5%) in Comparator arm. Incidence of ADRs were 5 (3.1%) in FDC of Pregabalin Prolonged Release and Etoricoxib and 2 (1.3%) in Etoricoxib arm. Out of total 11 TEAEs, eight were mild in nature and three were moderate in nature in test arm. In Etoricoxib arm, out of total 11 TEAEs, 10 were mild in nature and one was moderate in nature. All 22 AEs were recovered/resolved. None of the patients discontinued from the study due to AE. No serious AEs were reported in the study. Therefore, we can conclude that both treatments were safe and well tolerated.


Implications of study results
Chronic low back pain (LBP) has been shown to be the result of neuropathic as well as nociceptive pain mechanisms. Based on this evidence, it has been suggested that anticonvulsants in combination with either opioids, traditional nonsteroidal anti-inflammatory drugs or muscle relaxants could be useful in the treatment of this condition. Based on our study results we can say that FDC of Pregabalin Prolonged Release and Etoricoxib when given once daily for eight weeks in the patients of chronic low back pain can result into superior reduction in pain intensity and improvement in functional status of patients. Thus, in such patients giving FDC is a better option than giving Etoricoxib alone.

Conclusion
We have observed in our study that in patients having chronic low back pain when treated with FDC of Pregabalin Prolonged Release and Etoricoxib experienced a statistically and clinically significant benefit in pain intensity and functional status domain than those treated with Etoricoxib alone. Benefits were seen as early as 28 days. Overall the drug was found to be safe and well tolerated by the patients. Hence, FDC of Pregabalin Prolonged Release and Etoricoxib can be a better therapeutic option than administering Etoricoxib alone in patients with chronic low back pain by producing both better and early pain relief and improvement in disability.

 
Close