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Clinical Trial Results:
The metabolic impact of Darunavir/ritonavir maintenance monotherapy after successful viral suppression with standard Atripla in HIV-1-infected patients (MIDAs).

Summary
EudraCT number	2010-022120-72
Trial protocol	GB
Global end of trial date	17 Sep 2013

Results information
Results version number	v1(current)
This version publication date	06 Oct 2018
First version publication date	06 Oct 2018
Other versions
Summary report(s)	FINAL STUDY REPORT

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

JF-001

ISRCTN number

ISRCTN11504121

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Guy's and St Thomas' NHS Foundation Trust

Sponsor organisation address

Great Maze Pond, London, United Kingdom, SE19RT

Public contact

Dr Alastair Teague, Guy’s & St. Thomas’ NHS Foundation Trust, 0044 02071887188, alastair.teague@gstt.nhs.uk

Scientific contact

Dr Alastair Teague, Guy’s & St. Thomas’ NHS Foundation Trust, 0044 02071887188, alastair.teague@gstt.nhs.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

01 Jan 2014

Is this the analysis of the primary completion data?

Yes

Primary completion date

17 Sep 2013

Global end of trial reached?

Yes

Global end of trial date

17 Sep 2013

Was the trial ended prematurely?

Main objective of the trial

This project aims to assess the potential long-term advantages of switching HIV patients from the standard therapy (Atripla) to a different regime of treatment (darunavir 800 mg / ritonavir 100 mg). This will be assessed by measuring Vitamin D levels, calcium and phosphate homeostasis (balance), kidney (tubular) function, bone turnover and bone mineralisation, and HIV disease progression in all the patients who take part in the study.

Protection of trial subjects

Safety blood tests (FBC, Urea and electrolytes and liver function tests) and adherence review are incorporated into the visit schedule. Any abnormalities or concerns will be addressed immediately and reported.

Background therapy

Evidence for comparator

While Highly Active Anti-Retroviral Therapy (HAART) has dramatically reduced AIDS-related morbidity and mortality, the absence of HIV eradication with those drugs requires their prolonged used for a lifetime, making long-term toxicity a critical issue in the management of HIV-infected patients. Protease inhibitor (PI) monotherapy maintains plasma HIV-RNA suppression in a large proportion of patients already suppressed on a standard triple combination1. However, the more frequent occurrence of low-level viremia does not allow the use of such a strategy outside of clinical studies at this time. Darunavir has a high genetic barrier and low propensity to induce resistance-conferring mutations in cases of virologic failure. Early results showed non-inferiority with Darunavir/ritonovir monotherapy when compared to 2 NRTIs/ritonovir/darunavir [MONET and MONOI]. However, it remains unclear which patient populations might benefit most, and the potential risks and benefits associated with this therapeutic strategy remain to be defined. Hypothesis for this trial is that oosted Darunavir, given once a day as monotherapy, confers less toxicity than Atripla while maintaining undetectable HIV RNA levels

Actual start date of recruitment

02 May 2011

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 70

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Inclusion Criteria 1. Males and Females aged between 18 and 65 2. Documented Positive HIV 1-antibody test 3. Plasma HIV RNA <100 copies/ml and on Atripla for at least six months prior to study start 4. Agreeable NOT take vitamin D supplements for the duration of the study 5. Ability to give informed consent

Screening details

Inclusion Criteria  Males and Females aged between 18 and 65  Documented Positive HIV 1-antibody test  Plasma HIV RNA <100 copies/ml and on ATP for at least six months prior to study start  Agreeable NOT take vitamin D supplements for the duration of the study  Ability to give informed consent

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Randomization will take place on a 1:1 basis, with randomisation/allocation to study arm being determined using the MS Excel RAND() function

Are arms mutually exclusive

Yes

Atripla

Arm description

Atripla 1 tablet once daily for 48 weeks

Arm type

Active comparator

Investigational medicinal product name

Atripla

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Atripla® is efavirenz 600mg, emtricitabine 200mg with tenofovir disoproxil (as fumarate) 245mg. This will be taken orally once a day for 48 weeks.

Darunavir/ ritonovir

Arm description

Participants were randomised to receive Darunavir 800mg / ritonovir 100mg orally once per day for 48 weeks.

Arm type

Experimental

Investigational medicinal product name

Darunavir

Investigational medicinal product code

Other name

PREZISTA

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Darunavir 800mg once daily taken orally for 48 weeks

Investigational medicinal product name

Ritonovir

Investigational medicinal product code

Other name

Norvir

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Ritonovir 100mg taken orally once per day for 48 weeks

Number of subjects in period 1	Atripla	Darunavir/ ritonovir
Started	34	36
12 week visit	32	32
Completed	31	25
Not completed	3	11
Consent withdrawn by subject	1	6
Intolerance to IMP	-	2
Concomitant vitamin d therapy	2	-
Discontinued IMP	-	2
Adverse event, non-fatal	-	1

Baseline characteristics

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Reporting group title

Atripla

Reporting group description

Atripla 1 tablet once daily for 48 weeks

Reporting group title

Darunavir/ ritonovir

Reporting group description

Participants were randomised to receive Darunavir 800mg / ritonovir 100mg orally once per day for 48 weeks.

Reporting group values	Atripla	Darunavir/ ritonovir	Total
Number of subjects	34	36	70
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	34	36	70
From 65-84 years	0	0	0
85 years and over	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	41.6 ± 8.8	43.8 ± 9.2	-
Gender categorical
Units: Subjects
Female	7	9	16
Male	27	27	54

End points

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Reporting group title

Atripla

Reporting group description

Atripla 1 tablet once daily for 48 weeks

Reporting group title

Darunavir/ ritonovir

Reporting group description

Participants were randomised to receive Darunavir 800mg / ritonovir 100mg orally once per day for 48 weeks.

Primary: Mean change in Vitamin D level at Week 48 from baseline

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End point title

Mean change in Vitamin D level at Week 48 from baseline

End point description

Change in 25(OH)D at week 48

End point type

Primary

End point timeframe

From baseline to week 48

End point values	Atripla	Darunavir/ ritonovir
Number of subjects analysed	31	25
Units: mm/l
arithmetic mean (standard deviation)	1.2 ± 6	5 ± 5.9

Primary endpoint

Statistical analysis description

For sample size calculation, an increase of 15 nmol/L in 25(OH)D in the DRV/R arm compared to ATP was considered clinically relevant. With a 1:1 randomisation, 35 patients per arm and a continue-switch design, the study had 90% power to detect this difference. In addition, the study had 90% power to detect a fall in ALP of 10 IU/L in the DRV/r arm, compared with ATP. These calculations allowed for 5 patients in the DRV/r arm switching back to ATP for tolerability reasons.

Comparison groups

Atripla v Darunavir/ ritonovir

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.2

Method

Parameter type

Median difference (net)

Confidence interval

Variability estimate

Standard deviation

Notes
[1] - The study was not statistically powered to assess virological efficacy. In addition to the proportion of participants with two consecutive HIV viral load values > 50 copies/ml, an FDA snapshot analysis was performed at week 48. The frequencies of adverse events (AEs), AEs leading to discontinuation and laboratory test abnormalities were described by treatment arm. All analyses were performed on an intention to treat basis and conducted using Stata (version12).

Adverse events

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Timeframe for reporting adverse events

Duration of the trial and 4 weeks post last dose of IMP.

Adverse event reporting additional description

Darunavir is a licensed antiretroviral therapy which is well tolerated. The commonest side effects are nausea, headaches and diarrhoea which tend to be mild and self limiting. All side effects will be documented and Grade 2-4 AEs

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Group 1 ATRIPLA

Reporting group description

Atripla 1 tablet od for 48 weeks

Reporting group title

Group 2 DRV/r

Reporting group description

Darunavir 800mg od/ ritonovir 100mg od for 48 weeks

Serious adverse events	Group 1 ATRIPLA	Group 2 DRV/r
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 34 (8.82%)	3 / 36 (8.33%)
number of deaths (all causes)	0	0
number of deaths resulting from adverse events	0	0
Nervous system disorders
Seizure
Additional description: Seizures due to scar tissue after toxoplasmosis infection
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Concussion
subjects affected / exposed	1 / 34 (2.94%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Meningoencephalitis
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Uveitis
subjects affected / exposed	1 / 34 (2.94%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hyperparathypodism
subjects affected / exposed	1 / 34 (2.94%)	0 / 36 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Arthritic Sepsis
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Group 1 ATRIPLA	Group 2 DRV/r
Total subjects affected by non serious adverse events
subjects affected / exposed	30 / 34 (88.24%)	31 / 36 (86.11%)
Investigations
High HIV Viral Load
subjects affected / exposed	0 / 34 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	2
High Alkaline Phosphatase
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	1
High Cholesterol
subjects affected / exposed	5 / 34 (14.71%)	6 / 36 (16.67%)
occurrences all number	5	6
High LDL Cholesterol
subjects affected / exposed	3 / 34 (8.82%)	4 / 36 (11.11%)
occurrences all number	3	4
Low serum phophate
subjects affected / exposed	2 / 34 (5.88%)	3 / 36 (8.33%)
occurrences all number	2	3
Low white blood cells
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	1
High Gamma-GT
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	1
Nervous system disorders
Headache
subjects affected / exposed	0 / 34 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	2
Dizziness
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	1
Neurosensory alteration
subjects affected / exposed	0 / 34 (0.00%)	2 / 36 (5.56%)
occurrences all number	0	2
Syncope
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	1
Altered Mood
subjects affected / exposed	1 / 34 (2.94%)	0 / 36 (0.00%)
occurrences all number	1	0
Cognitive & Behavioral change
subjects affected / exposed	2 / 34 (5.88%)	0 / 36 (0.00%)
occurrences all number	2	0
General disorders and administration site conditions
Chills
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	1
Eye disorders
Altered vision
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	1
Gastrointestinal disorders
Bloating
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	1
Diarrhoea
subjects affected / exposed	1 / 34 (2.94%)	5 / 36 (13.89%)
occurrences all number	0	1
Nausea
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	1
Vomiting
subjects affected / exposed	0 / 34 (0.00%)	3 / 36 (8.33%)
occurrences all number	0	0
Bleeding Rectum
subjects affected / exposed	1 / 34 (2.94%)	0 / 36 (0.00%)
occurrences all number	1	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 34 (2.94%)	2 / 36 (5.56%)
occurrences all number	1	2
Fracture
subjects affected / exposed	1 / 34 (2.94%)	0 / 36 (0.00%)
occurrences all number	1	0
Infections and infestations
Sexually transmitted disease
subjects affected / exposed	0 / 34 (0.00%)	1 / 36 (2.78%)
occurrences all number	0	1
Gastroenteritis
subjects affected / exposed	3 / 34 (8.82%)	0 / 36 (0.00%)
occurrences all number	3	0
Upper respiratory tract infection
subjects affected / exposed	1 / 34 (2.94%)	0 / 36 (0.00%)
occurrences all number	1	0
Lower respiratory tract infection
subjects affected / exposed	2 / 34 (5.88%)	0 / 36 (0.00%)
occurrences all number	2	0

More information

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Were there any global substantial amendments to the protocol? Yes

18 Apr 2011

Addition of 4 exclusion criteria. Additional lab tests added and change in CI and PI for the study

08 Aug 2011

Amendment to the inclusion criteria. Amendment to the DXA scan from partial to full body scan and amendment to data analysis section of the protocol.

13 Mar 2012

changes and clarifications have been made to both the inclusion and exclusion criteria. change in the CI and PI

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

The study was not statistically powered to assess virological efficacy. In addition to the proportion of participants with two consecutive HIV viral load values > 50 copies/ml, an FDA snapshot analysis was performed at week 48. The frequencies of adv

http://www.ncbi.nlm.nih.gov/pubmed/26460504

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Clinical trials

Clinical Trial Results:
The metabolic impact of Darunavir/ritonavir maintenance monotherapy after successful viral suppression with standard Atripla in HIV-1-infected patients (MIDAs).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Mean change in Vitamin D level at Week 48 from baseline

Primary: Mean change in Vitamin D level at Week 48 from baseline

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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Clinical trials

Clinical Trial Results: The metabolic impact of Darunavir/ritonavir maintenance monotherapy after successful viral suppression with standard Atripla in HIV-1-infected patients (MIDAs).

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Mean change in Vitamin D level at Week 48 from baseline

Primary: Mean change in Vitamin D level at Week 48 from baseline

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
The metabolic impact of Darunavir/ritonavir maintenance monotherapy after successful viral suppression with standard Atripla in HIV-1-infected patients (MIDAs).