Hexaminolevulinate (HAL) Photodynamic Therapy (PDT) of Cervical Intraepithelial Neoplasia (CIN) Grade 1

• Sponsor: Photocure (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00708942
• Collaborator: (none)
• Enrollment: 83
• Locations: 5
• Arms: 5
• Duration (Months): 36
• Patients Per Site: 16.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The study will examine the effect of HAL vs placebo photodynamic therapy of low-grade cervical precancerous lesions (dysplasia) in women.

Condition or Disease	Intervention/Treatment	Phase
Cervical Intraepithelial Neoplasia	Drug: Hexaminolevulinate (HAL); Drug: Placebo; Drug: Hexaminolevulinate (HAL); Drug: Placebo	Phase 2

Detailed Description

Low-grade cervical intraepithelial neoplasia (CIN1) is caused by persistent HPV infection and may worse case develop into cancer. In most cases both the virus infection and lesions (CIN1) regress spontaneously, but must be followed up with gynecological examinations to ensure normalization. If further persistent disease and worsening to precancerous lesions (CIN2-3), the usual treatment is surgery, where one removes the tissue in the cervix where the CIN lesions are.

In this research study we will evaluate a new non-surgical treatment for CIN1 using hexaminolevulinate (HAL) photodynamic therapy (PDT). HAL PDT is the combination of a medication and a specific type of light to activate the drug. HAL PDT selectively removes CIN lesions while preserving normal tissue, thus this may be an alternative to frequent gynecological consultations and local surgery that may have undesirable side effects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 83 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Study of Hexaminolevulinate (HAL) Photodynamic Therapy (PDT) in Patients With Low-grade Cervical Intraepithelial Neoplasia (CIN1)
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 HAL suppository (single administration, HAL 100mg), laser illumination (50J/cm2)	Drug: Hexaminolevulinate (HAL); Drug: hexaminolevulinate (HAL) Suppository HAL 100 mg for 3-7 hours application
Placebo Comparator: 2 Placebo suppository (single administration), laser illumination (50J/cm2)	Drug: Placebo; Placebo suppository, for 3-7 hours application
No Intervention: 3
Active Comparator: 4 HAL ointment (5%, 100mg, single administration), LED diode illumination (50J/cm2)	Drug: Hexaminolevulinate (HAL); Drug: hexaminolevulinate (HAL) Ointment HAL 100 mg for 5 hours application
Placebo Comparator: 5 Placebo ointment (single administration), no illumination	Drug: Placebo; Placebo ointment for 5 hours application

Outcome Measures

Primary Outcome Measures

1. Complete Response Rate [6 month]

   Based on histology, cytology and HPV status. "Complete response" is defined as normal pathology, normal cytology and negative HPV.

Secondary Outcome Measures

1. Eradication of HPV [6 months]

   High risk HPV

2. Incidence of Patients With Adverse Events [3 months]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Satisfactory colposcopy examination

• Negative endocervical canal by colposcopy

• Ectocervical CIN1 as verified by local pathologist (biopsy).

• Colposcopical visible lesion at visit 2, before photoactivation

• Written Informed Consent signed

• Age 18 or above

Exclusion Criteria:

• Previous treatment of CIN or invasive disease or suspicion of either micro-invasive or invasive disease

• Malignant cells on cytology or histology

• Atypical glandular cells (AGC) or adenocarcinoma in situ (AIS) on cytology

• Suspicion of endocervical disease on colposcopy

• Current pelvic inflammatory disease, cervicitis, or other gynecological infection as per colposcopy and clinical examination

• Known or suspected porphyria

• Known allergy to hexaminolevulinate or similar compounds (e.g. methyl aminolevulinate or aminolevulinic acid)

• Use of heart pacemaker

• Pregnancy

• Nursing

• Childbirth or miscarriage within six weeks of enrolment - Known

• Participation in other "competitive" clinical studies either concurrently or within the last 30 days

• Risk of poor protocol compliance

• Not willing to use adequate birth control from screening until last PDT

• Subject is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Obstetrics and Gyneacology, Lille University Hospital	Lille		France
2	Department of Obstetrics and Gynecology	Hannover		Germany
3	Fritzøe klinikk	Larvik		Norway
4	Department of Obstetrics and Gynaecology, Ullevål University Hospital	Oslo		Norway
5	Medicus	Trondheim		Norway

Sponsors and Collaborators

• Photocure

Investigators

• Principal Investigator: Peter Hillemanns, MD, PhD, Medizinische Hochschule Hannover, Hannover, Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Photocure
• ClinicalTrials.gov Identifier: NCT00708942
• Other Study ID Numbers: PC CE201/08
• First Posted: Jul 3, 2008
• Last Update Posted: Apr 24, 2013
• Last Verified: Apr 1, 2013

• Keywords provided by Photocure: Cervical intraepithelial neoplasia (CIN)
• Additional relevant MeSH terms: Neoplasms; Carcinoma in Situ; Cervical Intraepithelial Neoplasia; Aminolevulinic Acid

Study Results

Participant Flow

Recruitment Details	All subjects recruited from medical clinics/hospitals. Start of recruitment arms 1-3: Jan 2009 End of recruitment arms 1-3: Feb 2010 Start of recruitment arms 4-5: Nov 2010 End of recruitment arms 4-5: Jul 2011
Pre-assignment Detail	Recruitment to part 1, including arms 1-3, completed before initiation of part 2 (arms 4-5). Arms 4 and 5 was a protocol amendment.

Arm/Group Title	Arm 1: HAL Suppository, Laser Illumination	Arm 2: Placebo Suppository, Laser Illumination	Arm 3: No Intervention	Arm 4: HAL Ointment, LED Diode Illumination	Arm 5: Placebo Ointment, no Illumination
Arm/Group Description
Period Title: Overall Study
STARTED	47	12	11	10	3
COMPLETED	40	11	9	10	2
NOT COMPLETED	7	1	2	0	1

Baseline Characteristics

Arm/Group Title	Arm 1: HAL Suppository, Laser Illumination	Arm 2: Placebo Suppository, Laser Illumination	Arm 3: No Intervention	Arm 4: HAL Ointment, LED Diode Illumination	Arm 5: Placebo Ointment, no Illumination	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	47	12	11	10	3	83
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	47 100%	12 100%	11 100%	10 100%	3 100%	83 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30.2 (6.9)	29.1 (4.7)	32.5 (8.4)	38.8 (9.4)	31.0 (4.0)	31.4 (7.1)
Sex: Female, Male (Count of Participants)
Female	47 100%	12 100%	11 100%	10 100%	3 100%	83 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
France	7 14.9%	1 8.3%	1 9.1%	1 10%	0 0%	10 12%
Norway	0 0%	1 8.3%	0 0%	9 90%	3 100%	13 15.7%
Germany	40 85.1%	10 83.3%	10 90.9%	0 0%	0 0%	60 72.3%

Outcome Measures

1. Primary Outcome

Title	Complete Response Rate
Description	Based on histology, cytology and HPV status. "Complete response" is defined as normal pathology, normal cytology and negative HPV.
Time Frame	6 month

Outcome Measure Data

Analysis Population Description

Per protocol population. Patients with major protocol violations excluded.

Arm/Group Title	Arm 1: HAL Suppository, Laser Illumination	Arm 2: Placebo Suppository, Laser Illumination	Arm 3: No Intervention	Arm 4: HAL Ointment, LED Diode Illumination	Arm 5: Placebo Ointment, no Illumination
Arm/Group Description
Measure Participants	35	10	6	10	3
Number [percentage of no. of patients analyzed]	57.1 (0)	40.0 (0)	0.0 (0)	90.0 (0)	33.3 (0)

2. Secondary Outcome

Title	Eradication of HPV
Description	High risk HPV
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Patients who were positive for high risk HPV at baseline

Arm/Group Title	Arm 1: HAL Suppository, Laser Illumination	Arm 2: Placebo Suppository, Laser Illumination	Arm 3: No Intervention	Arm 4: HAL Ointment, LED Diode Illumination	Arm 5: Placebo Ointment, no Illumination
Arm/Group Description
Measure Participants	20	7	3	4	3
Number [percentage of no. of patients analyzed]	60.0 (0)	28.6 (0)	100 (0)	50.0 (0)	33.3 (0)

3. Secondary Outcome

Title	Incidence of Patients With Adverse Events
Time Frame	3 months

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Arm 1: HAL Suppository, Laser Illumination	Arm 2: Placebo Suppository, Laser Illumination	Arm 3: No Intervention	Arm 4: HAL Ointment, LED Diode Illumination	Arm 5: Placebo Ointment, no Illumination
Arm/Group Description
Measure Participants	47	12	11	10	3
Number [percentage of no of patients analyzed]	44.7	25.0	18.2	70.0	66.7

Adverse Events

Arm/Group Title	Arm 1: HAL Suppository, Laser Illumination		Arm 2: Placebo Suppository, Laser Illumination		Arm 3: No Intervention		Arm 4: HAL Ointment, LED Diode Illumination		Arm 5: Placebo Ointment, no Illumination
Arm/Group Description
All Cause Mortality
	Arm 1: HAL Suppository, Laser Illumination		Arm 2: Placebo Suppository, Laser Illumination		Arm 3: No Intervention		Arm 4: HAL Ointment, LED Diode Illumination		Arm 5: Placebo Ointment, no Illumination
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1: HAL Suppository, Laser Illumination		Arm 2: Placebo Suppository, Laser Illumination		Arm 3: No Intervention		Arm 4: HAL Ointment, LED Diode Illumination		Arm 5: Placebo Ointment, no Illumination
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/47 (6.4%)		0/12 (0%)		1/11 (9.1%)		0/10 (0%)		0/3 (0%)
General disorders
Concomitant disease aggravated	1/47 (2.1%)	1	0/12 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/3 (0%)	0
Injury, poisoning and procedural complications
Jaw fracture	1/47 (2.1%)	1	0/12 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/3 (0%)	0
Psychiatric disorders
Schizophrenia	1/47 (2.1%)	1	0/12 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/3 (0%)	0
Depression	0/47 (0%)	0	0/12 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/3 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm 1: HAL Suppository, Laser Illumination		Arm 2: Placebo Suppository, Laser Illumination		Arm 3: No Intervention		Arm 4: HAL Ointment, LED Diode Illumination		Arm 5: Placebo Ointment, no Illumination
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/47 (34%)		3/12 (25%)		1/11 (9.1%)		6/10 (60%)		2/3 (66.7%)
Gastrointestinal disorders
Diarrhoea	0/47 (0%)	0	0/12 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	1/3 (33.3%)	1
Vomiting	0/47 (0%)	0	0/12 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	1/3 (33.3%)	1
General disorders
Pain	2/47 (4.3%)	2	0/12 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/3 (0%)	0
Discomfort	0/47 (0%)	0	0/12 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/3 (0%)	0
Immune system disorders
Seasonal allergy	2/47 (4.3%)	2	0/12 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/3 (0%)	0
Infections and infestations
Vaginal infection	2/47 (4.3%)	2	0/12 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/3 (0%)	0
Influenza	0/47 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	1/10 (10%)	1	0/3 (0%)	0
Urinary tract infection	0/47 (0%)	0	1/12 (8.3%)	1	0/11 (0%)	0	0/10 (0%)	0	0/3 (0%)	0
Pneumonia	0/47 (0%)	0	0/12 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/3 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle spasms	3/47 (6.4%)	4	0/12 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/3 (0%)	0
Back pain	0/47 (0%)	0	0/12 (0%)	0	0/11 (0%)	0	2/10 (20%)	2	0/3 (0%)	0
Nervous system disorders
Headache	2/47 (4.3%)	3	1/12 (8.3%)	1	0/11 (0%)	0	1/10 (10%)	1	1/3 (33.3%)	1
Reproductive system and breast disorders
Uterine pain	2/47 (4.3%)	2	1/12 (8.3%)	1	0/11 (0%)	0	0/10 (0%)	0	0/3 (0%)	0
Dysmenorrhoea	2/47 (4.3%)	2	0/12 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/3 (0%)	0
Vaginal discharge	1/47 (2.1%)	1	0/12 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/3 (0%)	0
Pelvic pain	0/47 (0%)	0	0/12 (0%)	0	0/11 (0%)	0	1/10 (10%)	1	0/3 (0%)	0
Vascular disorders
Haemorrhage	2/47 (4.3%)	2	0/12 (0%)	0	0/11 (0%)	0	0/10 (0%)	0	0/3 (0%)	0
Hypertension	0/47 (0%)	0	0/12 (0%)	0	1/11 (9.1%)	1	0/10 (0%)	0	0/3 (0%)	0

Limitations/Caveats

Slow recruitment lead to early terminaiton of the second part of the trial, including arms 4 and 5, after enrolment of 13 patients. No formal statistical analysis conducted on this part of the data.

More Information

Certain Agreements

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

The PI may publish the results from his/her site, provided that the publication does not disclose confidential information or interfere with sponsor's efforts to obtain patent protection for inventions. The sponsor must receive material for review not less than sixty (60) days prior to their proposed submission. In this multi center study, collective publications are anticipated. The PI must not independently publish the results of the Study before the first collective publication.