HALT: Hypertrophic Regression With N-Acetylcysteine in HCM

• Sponsor: The University of Texas Health Science Center, Houston (Other)
• Overall Status: Completed
• CT.gov ID: NCT01537926
• Collaborator: National Institutes of Health (NIH) (NIH)
• Enrollment: 42
• Location: 1
• Arms: 2
• Duration (Months): 60
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purpose of the sudy is to conduct a small study to gather the preliminary data for future lage scale clinical studies that will be designed test the potential beneficial effect of over-the counter study anti-oxidant drug called N-acetylcysteine (NAC) in patients with a heart muscle condition called Hypertrophic Cardiomyopathy (HCM). The present study is a pilot feasibility study, the investigators want to find out whether the investigators can recruit and retain patients with HCM in the study and whether these patients can tolerate this drug and can stay on one year. Likewise, the investigators want to find out any potential side effects that this drug might have and estimate whether it has any beneficial effects.

Condition or Disease	Intervention/Treatment	Phase
Hypertrophic Cardiomyopathy	Drug: N-acetylcysteine; Drug: Placebo	Phase 1

Detailed Description

The primary objective is to perform a pilot study in patients with hypertrophic cardiomyopathy (HCM) and mutations in genes encoding sarcomere proteins to assess safety and gather the pre-requisite data for subsequent robust randomized placebo-controlled efficacy studies with N-acetylcysteine (NAC). Data will be gathered on the recruitment, accrual, retention, and compliance rates of HCM patients randomized to treatment with a placebo or two escalating doses of NAC. Likewise, any potential side effects will be determined and the effect size of NAC on indices of cardiac hypertrophy will be estimated. HCM, the main focus of the study team's research during the past two decades, is the most common cause of sudden cardiac death (SCD) in the young and an important cause of morbidity in the elderly. Despite its clinical impact, there is no effective pharmacological therapy for HCM. None of the current pharmacological therapies reverses or attenuates cardiac hypertrophy or reduces the risk of SCD in adults. Cardiac hypertrophy, the quintessential clinical feature of human HCM, is a major determinant of morbidity and the risk of SCD. Regression of cardiac hypertrophy is expected to improve morbidity and decrease the risk of SCD in HCM, as observed upon regression of load-dependent cardiac hypertrophy. The study team has generated transgenic rabbit and mouse models of HCM and shown that cardiac hypertrophy and fibrosis could be reversed through genetic or pharmacological interventions. Results with NAC, a precursor to glutathione, the largest intracellular thiol pool against oxidative stress, were most promising. In three independent studies in two different transgenic models of HCM (rabbits and mouse), treatment with NAC completely reversed cardiac hypertrophy and fibrosis and improved indices of diastolic function. The ultimate goal of every physician-scientist is to apply the bench discoveries at the bedside. The study team proposes to test their findings in the animal models in humans with HCM caused by sarcomere protein mutations. The use of NAC is also supported by data showing increased oxidative stress in human HCM. Moreover, NAC has been used extensively in humans and has a well-established safety profile. Resources including patients with sarcomere protein mutations are available to successfully complete a randomized placebo-controlled (N=25) pilot study to test two escalating doses of NAC (N=50), administered for one year. The study aims to determine recruitment, accrual, retention and compliance rates; tolerability, safety and side effects; and estimate the effect size of NAC on the indices of cardiac hypertrophy at the baseline and after one year of treatment. Only HCM patients with sarcomere proteins mutations will be included to exclude phenocopy. The Core centers will interpret the phenotypic data to assure homogeneity. Data Coordinating Center will assist in the research design, planning and conduct of the study and analysis of the data. The findings will set the stage for large-scale robust randomized placebo-control efficacy studies.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Pilot Feasibility Study With N-acetylcystein (NAC) in Patients With HCM Caused by Sarcomere Proteins Mutations
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Dec 31, 2016
• Actual Study Completion Date: Dec 31, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: N-acetylcysteine (NAC) N-acetylcysteine 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days	Drug: N-acetylcysteine; NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.; Other Names: NAC
Placebo Comparator: Placebo Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days.	Drug: Placebo; sugar pill manufactured to minic NAC 600mg capsule; Other Names: Sugar pill

Outcome Measures

Primary Outcome Measures

1. Recruitment as Assessed by Number of Participants Who Enrolled to the Study [at the time of enrollment]

2. Retention as Assessed by Number of Participants Who Completed the Study [from baseline to 12 months]

3. Compliance as Assessed by Percentage of Pills Taken by Participant [from baseline to 12 months]

   Participants returned all pill bottles to the study team, and the number of pills not taken by the participant (that is, the number of pills remaining in the bottles) were counted. Compliance is reported as percentage of pills taken by the participant.

4. Number of Participants With Side Effects Attributable to the Intervention [from baseline to 12 months]

5. Interventricular Septal Thickness (IVST) as Assessed by Echocardiography [baseline]

6. Interventricular Septal Thickness (IVST) as Assessed by Echocardiography [12 months]

Secondary Outcome Measures

1. Left Ventricular End-systolic Diameter (LVESD) as Assessed by Echocardiography [12 months]

2. Left Ventricular End-systolic Diameter (LVESD) as Assessed by Echocardiography [baseline]

3. Left Ventricular Mass (LVM) as Assessed by Echocardiography [baseline]

   Left Ventricular Mass (LVM) is the weight of the left heart and is estimated from the echocardiographic measurements that include left ventricular wall thickness and the chamber diameter. The weight is calculated in grams and then normalized to body surface area (m^2), with LVM reported as g/m^2.

4. Left Ventricular Mass (LVM) as Assessed by Echocardiography [12 months]

   Left Ventricular Mass (LVM) is the weight of the left heart and is estimated from the echocardiographic measurements that include left ventricular wall thickness and the chamber diameter. The weight is calculated in grams and then normalized to body surface area (m^2), with LVM reported as g/m^2.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with primary cardiac hypertrophy, non-dilated LV cavity and preserved LV systolic function, hence, the diagnosis of HCM, who have at least an LV end diastolic (LVSD) wall thickness of at least 15 mm on a 2D echocardiogram and

• Known to have mutations in genes encoding sarcomeric proteins

Exclusion Criteria:

• Hypersensitivity to NAC

• Individuals younger than 18 years old (in the pilot study)

• Phenocopy conditions, diagnosed clinically or genetically

• Patients who have undergone transcatheter (alcohol) septal ablation within 6 months.

• Individuals (typically family members) with causal mutations but an LVSD wall thickness of <15 mm

• Patients with concomitant diseases such as:

• Significant coronary artery disease >70% luminal diameter stenosis in ny of the major coronary arteries (if known);

• Valvular heart diseases (more than mild aortic stenosis and mitral regurgitation, the latter judged to be due to primary mitral valve abnormalities);

• Uncontrolled hypertension, defined as systolic blood pressure of

• 140 mmHg and diastolic blood pressure of ≥90 mmHg on medication, mean of three measurements at rest);

• Other significant medical problems, such as moderate to severe chronic renal failure (GFR<45 ml/min/1.73m2), advanced liver disease, cancer, or other disabling conditions

• Pregnant women, nursing mothers and those who plan pregnancy during the study period

• Those with active asthma (albeit the concern is relevant to nebulizer form but not oral formulations)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Texas Health Science Center at Houston	Houston	Texas	United States	77030

Sponsors and Collaborators

• The University of Texas Health Science Center, Houston
• National Institutes of Health (NIH)

Investigators

• Principal Investigator: Ali J. Marian, MD, The University of Texas Health Science Center, Houston

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ali. J. Marian, Professor , Cardiovascular Genetics, IMM, The University of Texas Health Science Center, Houston
• ClinicalTrials.gov Identifier: NCT01537926
• Other Study ID Numbers: HALT-HCM; IR34HL105563
• First Posted: Feb 23, 2012
• Last Update Posted: Nov 2, 2021
• Last Verified: Nov 1, 2021

• Keywords provided by Ali. J. Marian, Professor , Cardiovascular Genetics, IMM, The University of Texas Health Science Center, Houston: HALT; HCM
• Additional relevant MeSH terms: Cardiomyopathies; Cardiomyopathy, Hypertrophic; Hypertrophy; Acetylcysteine; N-monoacetylcystine

Study Results

Participant Flow

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
Arm/Group Description	N-acetylcysteine (NAC) 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.	Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days. Placebo: sugar pill manufactured to minic NAC 600mg capsule
Period Title: Overall Study
STARTED	29	13
COMPLETED	24	11
NOT COMPLETED	5	2

Baseline Characteristics

Arm/Group Title	N-acetylcysteine (NAC)	Placebo	Total
Arm/Group Description	N-acetylcysteine 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.	Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days. Placebo: sugar pill manufactured to minic NAC 600mg capsule	Total of all reporting groups
Overall Participants	29	13	42
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	22 75.9%	12 92.3%	34 81%
>=65 years	7 24.1%	1 7.7%	8 19%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.7 (15.0)	47.6 (15.1)	49.15 (0.56)
Sex: Female, Male (Count of Participants)
Female	7 24.1%	3 23.1%	10 23.8%
Male	22 75.9%	10 76.9%	32 76.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 13.8%	1 7.7%	5 11.9%
Not Hispanic or Latino	25 86.2%	12 92.3%	37 88.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	29 100%	13 100%	42 100%

Outcome Measures

1. Primary Outcome

Title	Recruitment as Assessed by Number of Participants Who Enrolled to the Study
Time Frame	at the time of enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
Arm/Group Description	N-acetylcysteine 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.	Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days. Placebo: sugar pill manufactured to mimic NAC 600mg capsule
Measure Participants	29	13
Count of Participants [Participants]	29 100%	13 100%

2. Primary Outcome

Title	Retention as Assessed by Number of Participants Who Completed the Study
Time Frame	from baseline to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
Arm/Group Description	N-acetylcysteine 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.	Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days. Placebo: sugar pill manufactured to mimic NAC 600mg capsule
Measure Participants	29	13
Count of Participants [Participants]	24 82.8%	11 84.6%

3. Primary Outcome

Title	Compliance as Assessed by Percentage of Pills Taken by Participant
Description	Participants returned all pill bottles to the study team, and the number of pills not taken by the participant (that is, the number of pills remaining in the bottles) were counted. Compliance is reported as percentage of pills taken by the participant.
Time Frame	from baseline to 12 months

Outcome Measure Data

Analysis Population Description

Data are reported for participants for whom all pill bottles were returned to the study team. It was not known whether the returned bottles contained placebo or NAC; therefore, the data for both arms are reported together.

Arm/Group Title	All Participants
Arm/Group Description	N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days. OR Placebo: sugar pill manufactured to mimic NAC 600mg capsule
Measure Participants	30
Mean (Standard Deviation) [percentage of pills taken]	92 (0.0878)

4. Primary Outcome

Title	Number of Participants With Side Effects Attributable to the Intervention
Time Frame	from baseline to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
Arm/Group Description	N-acetylcysteine 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.	Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days. Placebo: sugar pill manufactured to mimic NAC 600mg capsule
Measure Participants	29	13
Count of Participants [Participants]	0 0%	0 0%

5. Primary Outcome

Title	Interventricular Septal Thickness (IVST) as Assessed by Echocardiography
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Data are reported for all participants who completed the study.

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
Arm/Group Description	N-acetylcysteine 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.	Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days. Placebo: sugar pill manufactured to mimic NAC 600mg capsule
Measure Participants	24	11
Mean (Standard Deviation) [millimeters (mm)]	18.88 (4.59)	18.00 (3.97)

6. Primary Outcome

Title	Interventricular Septal Thickness (IVST) as Assessed by Echocardiography
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Data are reported for all participants who completed the study.

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
Arm/Group Description	N-acetylcysteine 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.	Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days. Placebo: sugar pill manufactured to mimic NAC 600mg capsule
Measure Participants	24	11
Mean (Standard Deviation) [millimeters (mm)]	17.92 (3.3)	17.82 (4.87)

7. Secondary Outcome

Title	Left Ventricular End-systolic Diameter (LVESD) as Assessed by Echocardiography
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Data are reported for all participants who completed the study.

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
Arm/Group Description	N-acetylcysteine 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.	Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days. Placebo: sugar pill manufactured to mimic NAC 600mg capsule
Measure Participants	24	11
Mean (Standard Deviation) [millimeters (mm)]	21.88 (5.29)	21.55 (3.8)

8. Secondary Outcome

Title	Left Ventricular End-systolic Diameter (LVESD) as Assessed by Echocardiography
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Data are reported for all participants who completed the study.

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
Arm/Group Description	N-acetylcysteine 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.	Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days. Placebo: sugar pill manufactured to mimic NAC 600mg capsule
Measure Participants	24	11
Mean (Standard Deviation) [millimeters (mm)]	22.13 (6.06)	22.64 (5.16)

9. Secondary Outcome

Title	Left Ventricular Mass (LVM) as Assessed by Echocardiography
Description	Left Ventricular Mass (LVM) is the weight of the left heart and is estimated from the echocardiographic measurements that include left ventricular wall thickness and the chamber diameter. The weight is calculated in grams and then normalized to body surface area (m^2), with LVM reported as g/m^2.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Data are reported for all participants who completed the study.

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
Arm/Group Description	N-acetylcysteine 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.	Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days. Placebo: sugar pill manufactured to mimic NAC 600mg capsule
Measure Participants	24	11
Mean (Standard Deviation) [g/m^2]	269.65 (94.17)	292.80 (107.50)

10. Secondary Outcome

Title	Left Ventricular Mass (LVM) as Assessed by Echocardiography
Description	Left Ventricular Mass (LVM) is the weight of the left heart and is estimated from the echocardiographic measurements that include left ventricular wall thickness and the chamber diameter. The weight is calculated in grams and then normalized to body surface area (m^2), with LVM reported as g/m^2.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Data are reported for all participants who completed the study.

Arm/Group Title	N-acetylcysteine (NAC)	Placebo
Arm/Group Description	N-acetylcysteine 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.	Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days. Placebo: sugar pill manufactured to mimic NAC 600mg capsule
Measure Participants	24	11
Mean (Standard Deviation) [g/m^2]	281.98 (81.75)	290.44 (99.81)

Adverse Events

Time Frame	12 months
Arm/Group Title	N-acetylcysteine (NAC)		Placebo
Arm/Group Description	N-acetylcysteine 600mg by mouth every 12 hours for 90 days. N-acetylcysteine 1200mg by mouth every 12 hours for 270 days N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days.		Placebo 1 cap by mouth every 12 hours for 90 days. Placebo 2 caps by mouth every 12 hours for 270 days. N-acetylcysteine: NAC 600mg capsule or matching Placebo , 1 twice daily for 90 days, then increase to NAC 1,200mg or matching placebo, 2 capsules twice daily for 270 days. Placebo: sugar pill manufactured to mimic NAC 600mg capsule
All Cause Mortality
	N-acetylcysteine (NAC)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		0/13 (0%)
Serious Adverse Events
	N-acetylcysteine (NAC)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/29 (17.2%)		0/13 (0%)
General disorders
Chest pain	1/29 (3.4%)	1	0/13 (0%)	0
Nervous system disorders
Seizure	1/29 (3.4%)	1	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	2/29 (6.9%)	2	0/13 (0%)	0
Vascular disorders
Cerebrovascular accident	2/29 (6.9%)	2	0/13 (0%)	0
Other (Not Including Serious) Adverse Events
	N-acetylcysteine (NAC)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/29 (6.9%)		0/13 (0%)
Skin and subcutaneous tissue disorders
Skin Rash	2/29 (6.9%)	2	0/13 (0%)	2

Limitations/Caveats

The small sample size of the study prohibits from making firm conclusions about efficacy of NAC in hypertrophic cardiomyopathy (HCM).

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.