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The purpose of this study is to assess the safety and efficacy of the combination of IMM-101 with nivolumab.
This open-label study will assess the safety and efficacy of the combination of IMM-101 with nivolumab in patients with unresectable stage III, or stage IV melanoma who are either treatment-naive (cohort A) or whose disease has progressed during PD-1 blockade (cohort B). Ipilimumab may be used as a subsequent treatment in place of nivolumab alongside IMM-101 for patients in cohort B if their disease progresses on study. Eighteen patients will be enrolled into cohort A and 8 patients into cohort B.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| IMM-101 (and nivolumab or ipilimumab) | Experimental | Patients in cohort A were given IMM-101 in combination with nivolumab. Patients in cohort B who fail to respond to treatment with IMM-101 and nivolumab, and who meet certain criteria, have the option to change treatment on study to IMM-101 and ipilimumab. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Nivolumab | Drug | Nivolumab is to be administered as a 3 mg/kg IV infusion every two weeks in accordance with the prescribing information. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Safety and Tolerability of the Combination of IMM-101 + Nivolumab | Incidence, frequency and severity of treatment emergent adverse events (TEAEs) throughout the study. | From the point of Informed Consent until end of the study assessment (up to 84 weeks) or until withdrawal from the study. |
| Overall Response Rate | The primary endpoint of Overall Response Rate (ORR) is defined as the number of subjects with a Best Overall Response (BOR) of confirmed Complete Response (CR) or Partial Response (PR) divided by the number of subjects in the Intent-to-treat analysis set in each cohort of the study. The BOR will be determined once all the data up to and including the 12-month assessments for Cohort A or the 6-month assessment for Cohort B are available. It is defined as the best response designation based on confirmed responses determined by the investigator according to RECIST 1.1, recorded between the date of first postscreening scan and the date of last scan at/prior to the assessment at the 12-month assessment (Cohort A) and 6-month assessment/last assessment prior to change of treatment to IMM-101 + ipilimumab whichever is sooner (Cohort B). | From enrollment to end of study (18 months) or withdrawal, whichever was soonest |
| Measure | Description | Time Frame |
|---|---|---|
| Best Overall Response (BOR) Using RECIST 1.1 | Best Overall Response (BOR) is defined as the best response (complete or partial response, stable disease or progressive disease) designation based on confirmed responses determined by the investigator according to RECIST 1.1, recorded between the date of first postscreening scan and the date of last scan at/prior to the assessment at the 12-month assessment (Cohort A) and 6-month assessment/last assessment prior to change of treatment to IMM-101 + ipilimumab whichever is sooner (Cohort B).) Patients in cohort B who changed therapy without documented progression were censored at their last scan assessment prior to the change of therapy. |
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Key Inclusion Criteria:
For cohort A, the following key inclusion criteria apply:
1. Patient is treatment-naive (i.e. no prior systemic anticancer therapy for unresectable or metastatic melanoma).
For cohort B, the following key inclusion criteria apply:
1. Patient is either currently receiving treatment with an anti-PD-1 therapy (monotherapy or in combination with ipilimumab), for advanced melanoma and has progressive disease by RECIST 1.1 after 4 or more doses; or has previously received at least 4 doses of PD-1 targeted therapy, alone or in combination with ipilimumab, had disease progression by RECIST 1.1 during this therapy and has not received any further therapy for advanced melanoma.
Key Exclusion Criteria:
For cohort A, patients meeting the following key criteria are also ineligible to participate in this study:
1. Patient has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-PD ligand-1 (PD-L1), anti-PD-L2, anti-CD137 antibody, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) agent.
For cohort B, patients meeting the following key criteria are also ineligible to participate in this study:
1. Patient has received more than one treatment regimen for advanced (stage III/IV) disease prior to their anti PD-1 therapy.
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| Name | Affiliation | Role |
|---|---|---|
| Alberto Fusi | St George's University Hospitals NHS Foundation Trust | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| St George's University Hospitals NHS Foundation Trust | London | SW17 0QT | United Kingdom | |||
| The Christie Hospital |
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Twenty-two patients at 2 centres were consented and screened. Six patients failed to meet one or more of the specific inclusion criteria or met one or more exclusion criteria and were deemed screen failures.
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| ID | Title | Description |
|---|---|---|
| FG000 | IMM-101 (and Nivolumab or Ipilimumab) | Patients in cohort A were given IMM-101 in combination with nivolumab. Patients in cohort B who fail to respond to treatment with IMM-101 and nivolumab, and who meet certain criteria, have the option to change treatment on study to IMM-101 and ipilimumab. Nivolumab: Nivolumab is to be administered as a 3 mg/kg IV infusion every two weeks in accordance with the prescribing information. Ipilimumab: Ipilimumab, when used as subsequent treatment for patients in cohort B, is to be administered as a 3 mg/kg IV infusion over 90 minutes every three weeks for a maximum of 4 doses, in accordance with the prescribing information. IMM-101: A single 0.1 mL intradermal injection of IMM 101 (10 mg/mL) given every 2 weeks for the first 3 doses followed by a rest period of 4 weeks, then one dose every 2 weeks for the next 3 doses. This is followed by a dose every 4 weeks thereafter. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The baseline analysis population included all patients with confirmation of eligibility at Screening.
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| ID | Title | Description |
|---|---|---|
| BG000 | IMM-101 (and Nivolumab or Ipilimumab) | Patients in cohort A were given IMM-101 in combination with nivolumab. Patients in cohort B who fail to respond to treatment with IMM-101 and nivolumab, and who meet certain criteria, have the option to change treatment on study to IMM-101 and ipilimumab. Nivolumab: Nivolumab is to be administered as a 3 mg/kg IV infusion every two weeks in accordance with the prescribing information. Ipilimumab: Ipilimumab, when used as subsequent treatment for patients in cohort B, is to be administered as a 3 mg/kg IV infusion over 90 minutes every three weeks for a maximum of 4 doses, in accordance with the prescribing information. IMM-101: A single 0.1 mL intradermal injection of IMM 101 (10 mg/mL) given every 2 weeks for the first 3 doses followed by a rest period of 4 weeks, then one dose every 2 weeks for the next 3 doses. This is followed by a dose every 4 weeks thereafter. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Safety and Tolerability of the Combination of IMM-101 + Nivolumab | Incidence, frequency and severity of treatment emergent adverse events (TEAEs) throughout the study. | The Safety Analysis Set (SAF) included all patients who received at least one dose of IMM-101, irrespective of compliance with eligibility and other protocol criteria. | Posted | Count of Participants | Participants | From the point of Informed Consent until end of the study assessment (up to 84 weeks) or until withdrawal from the study. |
|
All adverse events (AEs) were recorded on the patient's electronic case report form (eCRF) from the time of informed consent until the end of study (18 months later) . All AEs were followed until resolution, death, or 30 days after the last administration of study treatment (whichever came first).
Incidence, frequency and severity of treatment-emergent adverse events (TEAEs; all TEAEs, serious adverse events (SAEs), treatment-related TEAEs, immune-related AEs, and TEAEs leading to IMM-101 discontinuation or study withdrawal).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | IMM-101 and Nivolumab |
Nivolumab was administered as a 3 mg/kg IV infusion every two weeks in accordance with the prescribing information. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Atrioventricular block | Cardiac disorders | MedDRA 21 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypertension | Vascular disorders | MedDRA 21 | Systematic Assessment |
The Overall Response Rate shows encouraging results in Cohort A with 73% of responses confirmed by subsequent scans (18% patients had a BOR (RECIST 1.1) of complete response (CR) and 55% of partial response (PR)). Limitations are the small sample size. This finding would need to be confirmed in a larger trial.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Trial Information Desk, | Immodulon Therapeutics Ltd | 0044 0203137 6346 | info@immodulon.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Dec 16, 2019 | Jan 17, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 16, 2020 | Jan 17, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D008545 | Melanoma |
| ID | Term |
|---|---|
| D018358 | Neuroendocrine Tumors |
| D017599 | Neuroectodermal Tumors |
| D009373 | Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
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| ID | Term |
|---|---|
| D000077594 | Nivolumab |
| D000074324 | Ipilimumab |
| C574749 | IMM-101 |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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|
| Ipilimumab | Drug | Ipilimumab, when used as subsequent treatment for patients in cohort B, is to be administered as a 3 mg/kg IV infusion over 90 minutes every three weeks for a maximum of 4 doses, in accordance with the prescribing information. |
|
|
| IMM-101 | Drug | A single 0.1 mL intradermal injection of IMM 101 (10 mg/mL) given every 2 weeks for the first 3 doses followed by a rest period of 4 weeks, then one dose every 2 weeks for the next 3 doses. This is followed by a dose every 4 weeks thereafter. |
|
|
| 18 months |
| Progression Free Survival (PFS) | Progression-free survival was defined as the time from Visit 1 (week 0) to the first confirmation of progression using RECIST 1.1 (confirmed or unconfirmed), or death from any cause (whichever occurred first). Progression was determined by the investigator using the CT or MRI scan or death due to any cause. Patients who died without reporting progression were considered to have progressed on the date of their death. Progression is defined by RECIST 1.1 guidelines as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. | From Visit 1 (week 0) and the first confirmation of progression using RECIST 1.1 (confirmed or unconfirmed), or death from any cause (whichever occurred first). |
| Overall Survival (OS) | Overall survival was defined as the time from Visit 1 (week 0) until date of death from any cause. OS was calculated for the entire study duration, where patients without a death date were right censored at the date the patient was last known to be alive. Post-study survival information was collected until database lock, for subjects completing or withdrawing from the study and included in the analysis. | Overall survival was defined as the time from Visit 1 (week 0) until the end of the study (80 weeks) or until the date of death from any cause. |
| Overall Survival (OS) at One Year | Number of patients surviving at leat 12 months | OS at 1 year was calculated after all patients had had the opportunity of 12 months treatment of study |
| Manchester |
| M20 4BX |
| United Kingdom |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| PD-L1 status in Cohort A patients only | Subgroups of patients in cohort A (n=11) were defined based on PD-L1 status (PD-L1 positive and PD-L1 negative/indeterminate) at Screening. For one patient PD-L1 status was unknown. | PDL-1 status was only determined in Cohort A patients (n=11) thus the Row population differs from the Overall population (n=16). | Number | participants |
|
|
|
| Primary | Overall Response Rate | The primary endpoint of Overall Response Rate (ORR) is defined as the number of subjects with a Best Overall Response (BOR) of confirmed Complete Response (CR) or Partial Response (PR) divided by the number of subjects in the Intent-to-treat analysis set in each cohort of the study. The BOR will be determined once all the data up to and including the 12-month assessments for Cohort A or the 6-month assessment for Cohort B are available. It is defined as the best response designation based on confirmed responses determined by the investigator according to RECIST 1.1, recorded between the date of first postscreening scan and the date of last scan at/prior to the assessment at the 12-month assessment (Cohort A) and 6-month assessment/last assessment prior to change of treatment to IMM-101 + ipilimumab whichever is sooner (Cohort B). | Intent-to-treat | Posted | Count of Participants | Participants | From enrollment to end of study (18 months) or withdrawal, whichever was soonest |
|
|
|
| Secondary | Best Overall Response (BOR) Using RECIST 1.1 | Best Overall Response (BOR) is defined as the best response (complete or partial response, stable disease or progressive disease) designation based on confirmed responses determined by the investigator according to RECIST 1.1, recorded between the date of first postscreening scan and the date of last scan at/prior to the assessment at the 12-month assessment (Cohort A) and 6-month assessment/last assessment prior to change of treatment to IMM-101 + ipilimumab whichever is sooner (Cohort B).) Patients in cohort B who changed therapy without documented progression were censored at their last scan assessment prior to the change of therapy. | Intent to treat population - all patients who received at least one dose of IMM-101 | Posted | Count of Participants | Participants | No | 18 months |
|
|
|
| Secondary | Progression Free Survival (PFS) | Progression-free survival was defined as the time from Visit 1 (week 0) to the first confirmation of progression using RECIST 1.1 (confirmed or unconfirmed), or death from any cause (whichever occurred first). Progression was determined by the investigator using the CT or MRI scan or death due to any cause. Patients who died without reporting progression were considered to have progressed on the date of their death. Progression is defined by RECIST 1.1 guidelines as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. | Intent-to-treat | Posted | Count of Participants | Participants | From Visit 1 (week 0) and the first confirmation of progression using RECIST 1.1 (confirmed or unconfirmed), or death from any cause (whichever occurred first). |
|
|
|
| Secondary | Overall Survival (OS) | Overall survival was defined as the time from Visit 1 (week 0) until date of death from any cause. OS was calculated for the entire study duration, where patients without a death date were right censored at the date the patient was last known to be alive. Post-study survival information was collected until database lock, for subjects completing or withdrawing from the study and included in the analysis. | Intent-to-treat | Posted | Count of Participants | Participants | Overall survival was defined as the time from Visit 1 (week 0) until the end of the study (80 weeks) or until the date of death from any cause. |
|
|
|
| Secondary | Overall Survival (OS) at One Year | Number of patients surviving at leat 12 months | Intent-to-treat | Posted | Count of Participants | Participants | OS at 1 year was calculated after all patients had had the opportunity of 12 months treatment of study |
|
|
|
| 8 |
| 16 |
| 12 |
| 16 |
| 16 |
| 16 |
| EG001 | IMM-101 and Ipilimumab | • Patients from Cohort B who failed to respond to nivolumab and met certain criteria had the option to switch to ipilimumab. Ipilimumab, when used as subsequent treatment for patients in Cohort B, was administered as a 3 mg/kg IV infusion over 90 minutes every three weeks for a maximum of 4 doses, in accordance with the prescribing information. | 1 | 1 | 1 | 1 | 1 | 1 |
| Pneumonia | Respiratory, thoracic and mediastinal disorders | MedDRA 21 | Systematic Assessment |
|
| Epistaxis | Blood and lymphatic system disorders | MedDRA 21 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 21 | Systematic Assessment |
|
| Chills | General disorders | MedDRA 21 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 21 | Systematic Assessment |
|
| Lethargy | General disorders | MedDRA 21 | Systematic Assessment |
|
| Pain | General disorders | MedDRA 21 | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA 21 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 21 | Systematic Assessment |
|
| Wrist fracture | Musculoskeletal and connective tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Spinal cord compression | Musculoskeletal and connective tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Cortisol deficiency | Endocrine disorders | MedDRA 21 | Systematic Assessment |
|
| Seasonal allergy | Immune system disorders | MedDRA 21 | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 21 | Systematic Assessment |
|
| Injection site erythema | General disorders | MedDRA 21 | Systematic Assessment |
|
| Pruritis | General disorders | MedDRA 21 | Systematic Assessment |
|
| Injection site swelling | General disorders | MedDRA 21 | Systematic Assessment |
|
| Injection site ulcer | General disorders | MedDRA 21 | Systematic Assessment |
|
| Chest pain | General disorders | MedDRA 21 | Systematic Assessment |
|
| influenza like illness | General disorders | MedDRA 21 | Systematic Assessment |
|
| Injection site vesicles | General disorders | MedDRA 21 | Systematic Assessment |
|
| Peripheral swelling | General disorders | MedDRA 21 | Systematic Assessment |
|
| Bartholins cyst | Reproductive system and breast disorders | MedDRA 21 | Systematic Assessment |
|
| Head injury | Injury, poisoning and procedural complications | MedDRA 21 | Systematic Assessment |
|
| Bundle branch block right | Cardiac disorders | MedDRA 21 | Systematic Assessment |
|
| Nasal polyps | Respiratory, thoracic and mediastinal disorders | MedDRA 21 | Systematic Assessment |
|
| Dyspnoea | Nervous system disorders | MedDRA 21 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 21 | Systematic Assessment |
|
| Hypoaesthesia | Nervous system disorders | MedDRA 21 | Systematic Assessment |
|
| Eye haemorrhage | Eye disorders | MedDRA 21 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA 21 | Systematic Assessment |
|
| Breath odour | Gastrointestinal disorders | MedDRA 21 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 21 | Systematic Assessment |
|
| Mouth Ulceration | Gastrointestinal disorders | MedDRA 21 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 21 | Systematic Assessment |
|
| Toothache | Gastrointestinal disorders | MedDRA 21 | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 21 | Systematic Assessment |
|
| Pain of skin | Skin and subcutaneous tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Pruritis | Skin and subcutaneous tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Psoriasis | Skin and subcutaneous tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Rash erythematous | Skin and subcutaneous tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Swelling face | Skin and subcutaneous tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Vitiligo | Skin and subcutaneous tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Pain in jaw | Musculoskeletal and connective tissue disorders | MedDRA 21 | Systematic Assessment |
|
| Hypothyroidism | Endocrine disorders | MedDRA 21 | Systematic Assessment |
|
| Hyperthyroidism | Endocrine disorders | MedDRA 21 | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 21 | Systematic Assessment |
|
| Coronavirus test positive | Investigations | MedDRA 21 | Systematic Assessment |
|
| Haemoglobin deecresed | Investigations | MedDRA 21 | Systematic Assessment |
|
| Vitamin D decreased | Investigations | MedDRA 21 | Systematic Assessment |
|
| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA 21 | Systematic Assessment |
|
| Cellulitis | Infections and infestations | MedDRA 21 | Systematic Assessment |
|
| Cystitis | Infections and infestations | MedDRA 21 | Systematic Assessment |
|
| Lower respiratory tract infection | Infections and infestations | MedDRA 21 | Systematic Assessment |
|
| Oral infection | Infections and infestations | MedDRA 21 | Systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA 21 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 21 | Systematic Assessment |
|
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| D009369 | Neoplasms |
| D009380 | Neoplasms, Nerve Tissue |
| D018326 | Nevi and Melanomas |
| D012878 | Skin Neoplasms |
| D009371 | Neoplasms by Site |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| Stable Disease |
|
| Disease Progression |
|
| >6 months but < or = to 9 months |
|
| >9 months but < or = to 12 months |
|
| >12 months but < or = to 18 months |
|
| .18 months |
|
| >6 months but < or = to 9 months |
|
| >9 months but < or = to 12 months |
|
| >12 months but < or = to 18 months |
|
| >18 months |
|