Two by Two Factorial Design using Metformin and Curcumin for Second Primary Head and Neck Cancer Prevention Trial

Document Type : Protocol


1 Department of Head Neck Oncology, Cytecare Cancer Hospital, Bangalore, India.

2 Department of Head and Neck Oncology, Sri Shnakara Caner Foundation, Bangalore, India.

3 Department of Head and Neck Oncology, Mazumdar Medical Center, Narayana Health City, Bangalore, India.

4 St. Johns’ Research Institute, Banglore, India.

5 Department of Head and Neck and Thoracic Oncology, Cancer Institute, Adyar, Chennai, India.

6 Department of Head and Neck Oncosurgery, Kailash Cancer Hospital and Research center, Goraj, Vadodara, India.

7 Department of Head and Neck Surgical Oncology, Tata Memorial Center, Navi Mumbai, Maharashtra, India.

8 Department of Head Neck Surgery and Oncology, Amrita Institute of Medical Science and Research Centre, Kochi, Kerala, India.

9 Head and Neck Oncology, Managing Director & Research Head, North East Cancer Hospital and Research Institute, Assam

10 Otorhinolaryngology and Head-Neck Surgery, Professor, All India Institute of Medical Sciences, Delhi, India.

11 Department of Surgical Oncology, Malabar Cancer Centre, Thalassery, Kerala, India.

12 Department of Head and Neck Cancer, HCG Cancer Centre, Ahmedabad, India.

13 Department of Surgical Oncology, Professor, IMS & SUM Hospital, Bhubaneswar, India.

14 Surgical Oncology, Associate Professor, Sher-i-Kashmir Institute of Medical Science, Srinagar, India.

15 Department of Otolaryngology, Professor and Head, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

16 Surgical Oncology, Associate Professor, Aster MIMS, Calicut, India.

17 Head and Neck Cancer Dept, Sr. Consultant Head & Neck Cancer Surgeon, Zydus Cancer Centre, Ahmedabad, India.

18 Head & Neck, Medical Director, Shankus Hospital Pvt. Ltd., Gujarat, India.

19 Department of Oncology, Cachar Cancer Hospital and Research Center, Silchar, Assam, India.

20 Integrated Head and Neck Oncology Program, Mazumdar Shaw Medical Foundation, Narayana Health City, Bangalore, India.

21 President, Head and Neck Cooperative Group, Department of Head and Neck Surgery Amrita Institute of Medical Sciences, Kochi, Kerala, India.


Objective: The 2x2 factorial design is an effective method that allows for multiple comparisons, especially in the context of interactions between different interventions, without substantially increasing the required sample size. In view of the considerable preclinical evidence for Curcumin and Metformin in preventing the development and progression of head and neck squamous cell carcinoma (HNSCC), this study describes the protocol of the clinical trial towards applying the drug combination in prevention of second primary tumors. Methods: We have applied the trial design to a large phase IIB/III double-blind, multi-centric, placebo-controlled, randomized clinical trial to determine the safety and efficacy of Metformin and Curcumin in the prevention of second primary tumours (SPT) of the aerodigestive tract following treatment of HNSCC (n=1,500) [Clinical Registry of India, CTRI/2018/03/012274]. Patients recruited in this trial will receive Metformin (with placebo), Curcumin (with placebo), Metformin, and Curcumin or placebo alone for a period of 36 months. The primary endpoint of this trial is the development of SPT, while the secondary endpoints are toxicities associated with the agents, incidence of recurrence, and identifying potential biomarkers. In this article, we discuss the 2x2 factorial design and how it applies to the head and neck cancer chemoprevention trial. Conclusion: 2x2 factorial design is an effective trial design for chemoprevention clinical trials where the effectiveness of multiple interventions needs to be tested parallelly. 


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