Study of Orofacial Pain and PropRANOlol

NCT02437383 | Completed Phase 2 Results DMC

• 3 other identifiers: 14-25261U01DE024169-0114-067-E
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 3

Brief Summary

Purpose: Primary: To evaluate the efficacy of extended-release (ER) propranolol compared to placebo in the reduction of a pain index in patients with temporomandibular disorder (TMD). Secondary: To determine if extended-release propranolol efficacy varies according to participants' catechol-O-methyltransferase (COMT) genetic polymorphisms and to investigate the efficacy of extended-release propranolol compared with placebo using secondary endpoints. Exploratory: To investigate whether the efficacy of extended-release propranolol in the reduction of the pain index varies according to participants' polymorphisms in 3 other genetic regions and according to various phenotypic characteristics. Participants: 200 patients with chronic TMD will be randomly assigned, in a 1:1 parallel, double-blind fashion, to receive either extended-release propranolol or placebo at one of three study sites: University of North Carolina-Chapel Hill School of Dentistry; University of Florida-Gainesville College of Dentistry; and the State University of New York at Buffalo School of Dental Medicine. Procedures (methods): Randomization will be to either propranolol or placebo. The 10-week study treatment period is divided into: 1 week of drug titration, 8 weeks of drug maintenance, and 1 week of drug tapering. The titration and tapering doses are 60 mg (capsules) once per day orally; the maintenance dose is 60 mg twice per day orally. Participants will attend 6 clinic visits over 12-15 weeks as follows: screening and baseline visit (Visit \[V\] 0, 7-21 days prior to V1); randomization and start of treatment (titration) (V1, study day 0); maintenance visit 2 (V2, 1 week post-randomization, study day 7+3); maintenance visit 3 (V3, 5 weeks post-randomization, study day 35 +/- 7); tapering visit (V4, 9 weeks post-randomization, study day 63 +/- 7); and tapering visit 5 (V5, 11 weeks post-randomization and 1 week after drug tapering ends, study day 77 +/- 7). Depending on the visit, procedures will include: reviews of medical history, weekly alcohol consumption, concomitant therapies and medications, adverse events, compliance, and eligibility; administration/review of questionnaires; blood draw; pregnancy test in women of childbearing potential; and dispensing of study drug.

Conditions

Temporomandibular Disorders

Outcome Measures

Primary Outcomes (1)

• Change in the Weekly Mean Pain Index After 9 Weeks of Treatment

  Weekly mean pain index computed as the arithmetic mean of daily pain index values during the week prior to randomization and prior to each study visit. Daily pain index is computed as pain intensity (0-100 numeric rating scale where 0 = "no pain" and 100 = "the most intense pain imaginable") multiplied by pain duration (0-100 percentage scale where percent = "percent of waking day you had facial pain") as reported in the Daily Symptom Diary and divided by 100. The pain index range is from 0 to 100. A higher score means a worse outcome.

  Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

Secondary Outcomes (32)

• Change in the Weekly Mean Pain Intensity After 9 Weeks of Treatment

  Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

• Change in the Weekly Mean Pain Duration After 9 Weeks of Treatment

  Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

• Change in the SF-McGill Pain Questionnaire Affective Component After 9 Weeks of Treatment

  Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

• Change in the SF-McGill Pain Questionnaire Sensory Component After 9 Weeks of Treatment

  Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

• Change in the SF-McGill Pain Questionnaire Present Facial Pain Intensity After 9 Weeks of Treatment

  Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

Other Outcomes (2)

• Change in the Weekly Mean Pain Index After 9 Weeks of Treatment Stratified Per Number of COMT LPS Haplotypes

  Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

• Change in the Weekly Mean Pain Index After 9 Weeks of Treatment Stratified Per Number of COMT Valine Alleles at rs4680

  Visit 1 (study day 0) and Visit 4 (study day 63 +/-7)

Study Arms (2)

Propranolol ER

ACTIVE COMPARATOR

Propranolol hydrochloride extended release (ER) capsules; 60 mg (Visit 1 and Visit 4); 120 mg (Visit 2 and Visit 3) given orally as: 60 mg once/day (Visit 1 and Visit 4) and 60 mg twice/day (Visit 2 and Visit 3).

Drug: Propranolol ER

Placebo

PLACEBO COMPARATOR

Capsules, identical in appearance to active comparator (propranolol), to be administered orally in exactly the same manner as propranolol at Visit 1 (once/day), Visit 2 (twice/day), Visit 3 (twice/day), and Visit 4 (once/day).

Drug: Placebo

Interventions

Propranolol ER DRUG

Capsules given orally according to schedule at Visit 1, Visit 2, Visit 3, and Visit 4.

Also known as: Inderal (long-acting)

Propranolol ER

Placebo DRUG

Gelatin capsules with a microcrystalline cellulose filler manufactured to mimic propranolol ER 60 mg capsules

Also known as: Sugar pill

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnostic criteria for TMD: Group II, Masticatory Muscle Disorders, Myalgia
• Facial pain for at least 3 months (and at least 10 of the last 30 days at Visit 0)
• Average pain intensity rating ≥30 (0-100 numeric rating scale) over the past week or average daily pain intensity rating ≥30 on the same scale on at least 3 days over the past week
• Agrees to terms for continuing/discontinuing certain prescription/over-the-counter pain medications throughout participation
• Agrees to not commence new prescription medication, injection therapy, occlusal splint therapy or certain other pain management techniques throughout participation
• Agrees to limit consumption of alcohol to no more than 7 drinks/week (females) and no more than 14 drinks/week (males) throughout participation
• If a female of childbearing potential, agrees to use of contraception (licensed hormonal method, intrauterine device, condoms with contraceptive foam, abstinence, or partner vasectomy) throughout participation
• Able to understand and comply with study procedures and provide written informed consent

You may not qualify if:

• History of congestive heart failure or certain cardiac conditions including coronary artery disease, uncontrolled hypertension, or hypotension
• Bronchial asthma, nonallergic bronchospasm, renal failure or dialysis, diabetes mellitus, hyperthyroidism, fibromyalgia, or uncontrolled seizures
• Currently taking a β-blocker or certain other medications including haloperidol, intravenous verapamil, or reserpine
• Currently taking an opioid medication
• Daily prescription medication, occlusal splint therapy, or an investigational drug or treatment for pain management within past 30 days
• Injection therapy or certain other pain management techniques within last 2 weeks
• Facial trauma or orofacial surgery within past 6 weeks
• Active orthodontic treatment
• History of major depression or other psychiatric disorder requiring hospitalization within past 6 months
• Treatment for drug or alcohol abuse within the last year
• Smokes 25 or more cigarettes/day
• Currently receiving chemotherapy or radiation therapy
• Pregnant or breastfeeding

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• University of Florida: collaborator
• Rho, Inc.: collaborator
• National Institutes of Health (NIH): collaborator
• National Institute of Dental and Craniofacial Research (NIDCR): collaborator
• State University of New York at Buffalo: collaborator

Study Sites (3)

University of Florida-Gainesville College of Dentistry

Gainesville, Florida, 32610-0404, United States

Location

University at Buffalo School of Dental Medicine

Buffalo, New York, 14214, United States

Location

University of North Carolina at Chapel Hill School of Dentistry

Chapel Hill, North Carolina, 27599, United States

Location

Related Publications (8)

• Tchivileva IE, Lim PF, Smith SB, Slade GD, Diatchenko L, McLean SA, Maixner W. Effect of catechol-O-methyltransferase polymorphism on response to propranolol therapy in chronic musculoskeletal pain: a randomized, double-blind, placebo-controlled, crossover pilot study. Pharmacogenet Genomics. 2010 Apr;20(4):239-48. doi: 10.1097/FPC.0b013e328337f9ab.

  PMID: 20216107 BACKGROUND

• Gursoy S, Erdal E, Herken H, Madenci E, Alasehirli B, Erdal N. Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome. Rheumatol Int. 2003 May;23(3):104-7. doi: 10.1007/s00296-002-0260-5. Epub 2002 Oct 22.

  PMID: 12739038 BACKGROUND

• Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet. 2005 Jan 1;14(1):135-43. doi: 10.1093/hmg/ddi013. Epub 2004 Nov 10.

  PMID: 15537663 BACKGROUND

• Tchivileva IE, Ohrbach R, Fillingim RB, Lin FC, Lim PF, Arbes SJ Jr, Slade GD. Clinical, psychological, and sensory characteristics associated with headache attributed to temporomandibular disorder in people with chronic myogenous temporomandibular disorder and primary headaches. J Headache Pain. 2021 May 22;22(1):42. doi: 10.1186/s10194-021-01255-1.

  PMID: 34022805 DERIVED

• Tchivileva IE, Ohrbach R, Fillingim RB, Lim PF, Giosia MD, Ribeiro-Dasilva M, Campbell JH, Hadgraft H, Willis J, Arbes SJ Jr, Slade GD. Effect of comorbid migraine on propranolol efficacy for painful TMD in a randomized controlled trial. Cephalalgia. 2021 Jun;41(7):839-850. doi: 10.1177/0333102421989268. Epub 2021 Feb 9.

  PMID: 33560875 DERIVED

• Slade GD, Fillingim RB, Ohrbach R, Hadgraft H, Willis J, Arbes SJ Jr, Tchivileva IE. COMT Genotype and Efficacy of Propranolol for TMD Pain: A Randomized Trial. J Dent Res. 2021 Feb;100(2):163-170. doi: 10.1177/0022034520962733. Epub 2020 Oct 8.

  PMID: 33030089 DERIVED

• Tchivileva IE, Hadgraft H, Lim PF, Di Giosia M, Ribeiro-Dasilva M, Campbell JH, Willis J, James R, Herman-Giddens M, Fillingim RB, Ohrbach R, Arbes SJ Jr, Slade GD. Efficacy and safety of propranolol for treatment of temporomandibular disorder pain: a randomized, placebo-controlled clinical trial. Pain. 2020 Aug;161(8):1755-1767. doi: 10.1097/j.pain.0000000000001882.

  PMID: 32701836 DERIVED

• Sanders AE, Slade GD, Fillingim RB, Ohrbach R, Arbes SJ Jr, Tchivileva IE. Effect of Treatment Expectation on Placebo Response and Analgesic Efficacy: A Secondary Aim in a Randomized Clinical Trial. JAMA Netw Open. 2020 Apr 1;3(4):e202907. doi: 10.1001/jamanetworkopen.2020.2907.

  PMID: 32297945 DERIVED

MeSH Terms

Conditions

Temporomandibular Joint Disorders

Interventions

Propranolol; Sugars

Condition Hierarchy (Ancestors)

Craniomandibular Disorders; Mandibular Diseases; Jaw Diseases; Musculoskeletal Diseases; Joint Diseases; Muscular Diseases; Stomatognathic Diseases

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Carbohydrates

Results Point of Contact

• Title: Dr. Inna E. Tchivileva
• Organization: University of North Carolina at Chapel Hill

inna_tchivileva@unc.edu

1 919 537 3291

Study Officials

• Inna E. Tchivileva, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

• Roger B. Fillingim, PhD

  University of Florida-Gainesville College of Dentistry

  PRINCIPAL INVESTIGATOR

• Richard Ohrbach, DDS, PhD

  University at Buffalo School of Dental Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 4, 2015
• First Posted: May 7, 2015
• Study Start: August 20, 2015
• Primary Completion: April 4, 2018
• Study Completion: April 25, 2018
• Last Updated: May 21, 2019
• Results First Posted: May 21, 2019

Record last verified: 2018-04

Locations

US (3)