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

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.

Study Overview

• Status: Completed
• Conditions: COPD; COPD Exacerbation; Pollution; Exposure; COPD Exacerbation Acute; Pollution Related Respiratory Disorder
• Intervention / Treatment: Drug: Theophylline ER; Other: Standard of Care Treatment; Drug: Placebo oral tablet

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Trishul Siddharthan, MD; Phone Number: 305-243-6388; Email: t.siddharthan@umiami.edu

Study Locations

• Uganda
  • Kampala, Uganda
    • Makerere Lung Institute
  • Nakaseke, Uganda
    • Nakaseke Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

Exclusion Criteria:

1. Plans to move within one year
2. Uncontrolled hypertension
3. Pregnancy (assessed by urine pregnancy test among women of childbearing age/menstrual history)
4. Current use of chronic respiratory medications (Long acting Beta 2 Antagonists (LABA), Long-acting muscarinic antagonist (LAMA), inhaled corticosteroid (ICS))
5. History of post-treatment pulmonary tuberculosis
6. ≥10 pack year tobacco smoking history
7. Known intolerance or contraindication to theophylline.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low-dose Theophylline Group; 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; 200 mg extended release (ER) low-dose theophylline taken orally daily; Other Names: Low-dose Theophylline; Other: Standard of Care Treatment; Per World Health Organization (WHO) guidelines for management of Chronic Obstructive Pulmonary Disease (COPD) treatment
Placebo Comparator: Placebo Group; 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.	Other: Standard of Care Treatment; Per World Health Organization (WHO) guidelines for management of Chronic Obstructive Pulmonary Disease (COPD) treatment; Drug: Placebo oral tablet; Manufactured methylcellulose placebo tablet taken orally daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 to 6 months, Baseline to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in forced expiratory volume in one second (FEV1)	FEV1 (L) as measured through spirometry	Baseline to 6 months, Baseline to 1 year
Change in forced vital capacity (FVC)	FVC (L) as measured through spirometry	Baseline to 6 months, Baseline to 1 year
Change in peak expiratory flow (PEF)	PEF (L/min) as measured through spirometry	Baseline to 6 months, Baseline to 1 year
Change in blood levels of high sensitivity C reactive protein (hs-CRP)	Blood levels of hs-CRP (mg/L)	Baseline to 6 months, Baseline to 1 year
Change in blood levels of fibrinogen	Blood levels of fibrinogen (mg/dL)	Baseline to 6 months, Baseline to 1 year
Change in Short Form 36 (SF-36) Questionnaire Scores	The SF-36 consists of eight scaled domains (vitality, physical functioning, body pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning, mental health) each transformed into a 0-100 scale. Lower scores signify higher levels of disability.	Baseline to 6 months, Baseline to 1 year

Collaborators and Investigators

• Sponsor: University of Miami
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Trishul Siddharthan, MD, University of Miami

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2021
• Primary Completion (Actual): October 17, 2023
• Study Completion (Actual): December 15, 2023

Study Registration Dates

• First Submitted: June 10, 2019
• First Submitted That Met QC Criteria: June 11, 2019
• First Posted (Actual): June 12, 2019

Study Record Updates

• Last Update Posted (Actual): December 28, 2023
• Last Update Submitted That Met QC Criteria: December 27, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Biomass Associated COPD; Low-dose Theophylline
• Additional Relevant MeSH Terms: Pathologic Processes; Lung Diseases; Disease Attributes; Lung Diseases, Obstructive; Chronic Disease; Pulmonary Disease, Chronic Obstructive; Respiration Disorders; Respiratory Tract Diseases; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Purinergic Antagonists; Purinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Theophylline
• Other Study ID Numbers: 20201523; 1K23HL146946-01 (U.S. NIH Grant/Contract); IRB00209008 (Other Identifier: Johns Hopkins University)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No