Effectiveness of Low-Dose Theophylline for the Management of Biomass-Associated COPD

NCT03984188 | Completed Phase 3 Results

• 3 other identifiers: 202015231K23HL146946-01IRB00209008
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 2

Brief Summary

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide, and over 90% of COPD-related deaths occurring in low- and middle-income countries (LMICs). Household air pollution (HAP) - from burning solid fuels such as wood, dung, agricultural crop waste, and coal for energy - is the primary risk factor for COPD in these settings. Biomass-related COPD has a distinct histopathology, phenotype and inflammatory profile when compared to tobacco mediated COPD. Despite the high global burden of biomass-related disease, little is known about the effectiveness of pharmacotherapies for biomass-related COPD; to date, no clinical trials have focused specifically on treatment of biomass-related COPD. This study proposes to assess the health impact of biomass-related COPD and test the effectiveness of low dose theophylline compared to standard therapy among adults with biomass-related COPD in Uganda with the aim to assess whether low-dose theophylline improves respiratory symptoms, decreases the inflammatory profile of serum biomarkers and whether administration attenuates the effect of HAP on lung function. The study additionally aims to assess whether low-dose theophylline is a cost-effective intervention based on the incremental cost-effectiveness ratio and a range of willingness to pay thresholds.

Conditions

COPD; COPD Exacerbation; COPD Exacerbation Acute; Pollution Related Respiratory Disorder; Pollution; Exposure

Keywords

Biomass Associated COPD; Low-dose Theophylline

Outcome Measures

Primary Outcomes (1)

• Change in St. George Respiratory Questionnaire (SGRQ) Scores

  The SGRQ comprises of 50 items and consists of two parts. The first part pertains to symptoms and the second pertains to functional status as well as social and psychological impact of disease. Overall scores ranges between 0 and 100 with higher scores indicating more limitations.

  Baseline, 1 year

Secondary Outcomes (5)

• Change in Forced Expiratory Volume in One Second (FEV1)

  Baseline, 1 year

• Change in Forced Vital Capacity (FVC)

  Baseline, 1 year

• Change in Forced Vital Capacity (FVC)

  Baseline, 6 months

• Change in St. George Respiratory Questionnaire (SGRQ) Scores

  Baseline, 6 months

• Change in Forced Expiratory Volume in One Second (FEV1)

  Baseline, 6 months

Study Arms (2)

Low-dose Theophylline Group

EXPERIMENTAL

Participant in this group will receive low-dose theophylline in addition to standard care, per World Health Organization (WHO) guidelines for management of Chronic Obstructive Pulmonary Disease (COPD) treatment, over a one year period.

Drug: Theophylline ER; Other: Standard of Care Treatment

Placebo Group

PLACEBO COMPARATOR

Participant in this group will receive a placebo in addition to standard care, per World Health Organization (WHO) guidelines for management of Chronic Obstructive Pulmonary Disease (COPD) treatment.

Drug: Placebo oral tablet; Other: Standard of Care Treatment

Interventions

Theophylline ER DRUG

200 mg extended release (ER) low-dose theophylline taken orally daily

Also known as: Low-dose Theophylline

Low-dose Theophylline Group

Placebo oral tablet DRUG

Manufactured methylcellulose placebo tablet taken orally daily

Placebo Group

Standard of Care Treatment OTHER

Per World Health Organization (WHO) guidelines for management of Chronic Obstructive Pulmonary Disease (COPD) treatment

Low-dose Theophylline Group; Placebo Group

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 40 years
• Full-time resident of study area
• Post-bronchodilator FEV1/FVC \< the lower limit of normal of the Global Lung Initiative Mixed Ethnic reference population
• Grade B-D COPD
• Daily biomass exposure

You may not qualify if:

• Plans to move within one year
• Uncontrolled hypertension
• Pregnancy (assessed by urine pregnancy test among women of childbearing age/menstrual history)
• Current use of chronic respiratory medications (Long acting Beta 2 Antagonists (LABA), Long-acting muscarinic antagonist (LAMA), inhaled corticosteroid (ICS))
• History of post-treatment pulmonary tuberculosis
• ≥10 pack year tobacco smoking history
• Known intolerance or contraindication to theophylline.

Sponsors & Collaborators

• University of Miami: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (2)

Makerere Lung Institute

Kampala, Uganda

Location

Nakaseke Hospital

Nakaseke, Uganda

Location

Related Publications (12)

• Bonjour S, Adair-Rohani H, Wolf J, Bruce NG, Mehta S, Pruss-Ustun A, Lahiff M, Rehfuess EA, Mishra V, Smith KR. Solid fuel use for household cooking: country and regional estimates for 1980-2010. Environ Health Perspect. 2013 Jul;121(7):784-90. doi: 10.1289/ehp.1205987. Epub 2013 May 3.

  PMID: 23674502 BACKGROUND

• Siddharthan T, Grigsby MR, Goodman D, Chowdhury M, Rubinstein A, Irazola V, Gutierrez L, Miranda JJ, Bernabe-Ortiz A, Alam D, Kirenga B, Jones R, van Gemert F, Wise RA, Checkley W. Association between Household Air Pollution Exposure and Chronic Obstructive Pulmonary Disease Outcomes in 13 Low- and Middle-Income Country Settings. Am J Respir Crit Care Med. 2018 Mar 1;197(5):611-620. doi: 10.1164/rccm.201709-1861OC.

  PMID: 29323928 BACKGROUND

• Moran-Mendoza O, Perez-Padilla JR, Salazar-Flores M, Vazquez-Alfaro F. Wood smoke-associated lung disease: a clinical, functional, radiological and pathological description. Int J Tuberc Lung Dis. 2008 Sep;12(9):1092-8.

  PMID: 18713510 BACKGROUND

• Perez-Padilla R, Ramirez-Venegas A, Sansores-Martinez R. Clinical Characteristics of Patients With Biomass Smoke-Associated COPD and Chronic Bronchitis, 2004-2014. Chronic Obstr Pulm Dis. 2014 May 6;1(1):23-32. doi: 10.15326/jcopdf.1.1.2013.0004.

  PMID: 28848808 BACKGROUND

• Ait-Khaled N, Enarson D, Bousquet J. Chronic respiratory diseases in developing countries: the burden and strategies for prevention and management. Bull World Health Organ. 2001;79(10):971-9. Epub 2001 Nov 1.

  PMID: 11693980 BACKGROUND

• Beran D, Zar HJ, Perrin C, Menezes AM, Burney P; Forum of International Respiratory Societies working group collaboration. Burden of asthma and chronic obstructive pulmonary disease and access to essential medicines in low-income and middle-income countries. Lancet Respir Med. 2015 Feb;3(2):159-170. doi: 10.1016/S2213-2600(15)00004-1.

  PMID: 25680912 BACKGROUND

• Barnes PJ. Theophylline in chronic obstructive pulmonary disease: new horizons. Proc Am Thorac Soc. 2005;2(4):334-9; discussion 340-1. doi: 10.1513/pats.200504-024SR.

  PMID: 16267358 BACKGROUND

• Ford PA, Durham AL, Russell RE, Gordon F, Adcock IM, Barnes PJ. Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest. 2010 Jun;137(6):1338-44. doi: 10.1378/chest.09-2363. Epub 2010 Mar 18.

  PMID: 20299628 BACKGROUND

• Rivera RM, Cosio MG, Ghezzo H, Salazar M, Perez-Padilla R. Comparison of lung morphology in COPD secondary to cigarette and biomass smoke. Int J Tuberc Lung Dis. 2008 Aug;12(8):972-7.

  PMID: 18647460 BACKGROUND

• Mendis S, Fukino K, Cameron A, Laing R, Filipe A Jr, Khatib O, Leowski J, Ewen M. The availability and affordability of selected essential medicines for chronic diseases in six low- and middle-income countries. Bull World Health Organ. 2007 Apr;85(4):279-88. doi: 10.2471/blt.06.033647.

  PMID: 17546309 BACKGROUND

• Zhou Y, Wang X, Zeng X, Qiu R, Xie J, Liu S, Zheng J, Zhong N, Ran P. Positive benefits of theophylline in a randomized, double-blind, parallel-group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology. 2006 Sep;11(5):603-10. doi: 10.1111/j.1440-1843.2006.00897.x.

  PMID: 16916334 BACKGROUND

• Siddharthan T, Pollard SL, Jackson P, Robertson NM, Wosu AC, Rahman N, Padalkar R, Sekitoleko I, Namazzi E, Alupo P, Hurst JR, Kalyesubula R, Dowdy D, Wise R, Barnes PJ, Checkley W, Kirenga B. Effectiveness of low-dose theophylline for the management of biomass-associated COPD (LODOT-BCOPD): study protocol for a randomized controlled trial. Trials. 2021 Mar 16;22(1):213. doi: 10.1186/s13063-021-05163-2.

  PMID: 33726828 DERIVED

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

Theophylline

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Xanthines; Alkaloids; Heterocyclic Compounds; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Trishul Siddharthan
• Organization: University of Miami

tsiddhar@miami.edu

305-243-6388

Study Officials

• Trishul Siddharthan, MD

  University of Miami

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Clinical

Study Record Dates

• First Submitted: June 10, 2019
• First Posted: June 12, 2019
• Study Start: February 23, 2021
• Primary Completion: October 17, 2023
• Study Completion: December 15, 2023
• Last Updated: November 15, 2024
• Results First Posted: October 29, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

UG (2)